Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].BrC(Br)(Br)Br.[NH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:24][O:25][P:26]([O-:29])[O:27][CH3:28]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C(Cl)Cl>[CH:15]([C:13]1[CH:12]=[CH:11][C:10]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[C:9]([NH:8][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24])[CH:14]=1)([CH3:17])[CH3:16]
Reactant: COP([O-])OC
Reactant: CC(C)c1ccc(N2CCOCC2)c(N)c1
Agent: BrC(Br)(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: COP(=O)(Nc1cc(C(C)C)ccc1N1CCOCC1)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a stirred solution of 10 ml. of methylene dichloride, 7 ml. of 20% aqueous sodium hydroxide, 3 g. of tetrabromomethane, and 0.2 g. of triethylbenzylammonium chloride was slowly added a solution of 4.0 g. (0.018 moles) of 4-(2-amino-4-isopropylphenyl)morpholine and 2.0 g. of dimethylphosphite dissolved in about 20 ml. of methylene dichloride. The reaction was exothermic and cooling by an ice bath was required. After stirring at ambient temperature for 18 hours, GC analysis indicated the reaction was about 30% complete. Accordingly, a 10% excess of the dimethylphosphite (0.2 g.) and an additional 0.3 g. of tetrabromomethane was added and stirring of the reaction mixture continued overnight. The mixture was then poured into an ice-water solution and the methylene dichloride layer separated. The aqueous layer was extracted twice with methylene dichloride and the combined methylene dichloride phases were rinsed thrice with water. After drying over anhydrous sodium sulfate, the methylene dichloride solution was filtered and evaporated under reduced pressure. The residue was eluted through a silica gel column using 99.5% methylene dichloride and 0.5% methanol to separate the product which was isolated from the solvent as a tan solid (2.2 g.; 37% yield); melting point 97°-98° C.
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:44]([F:45])=[CH:43][C:42]([S:46]([CH3:48])=[O:47])=[CH:41][C:40]=4[F:49])[N:33]=3)=[O:31])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>CO.C1COCC1.C(Cl)Cl>[NH2:21][C@H:16]1[CH2:17][C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH:29][C:30]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[C:34]([C:39]4[C:40]([F:49])=[CH:41][C:42]([S:46]([CH3:48])=[O:47])=[CH:43][C:44]=4[F:45])[N:33]=3)=[O:31])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](N)CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(S(C)=O)cc4F)n3)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-{(3S,5R)-3-[(tert-Butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (3.0 mg, 0.0043 mmol) was dissolved in MeOH (0.02 mL) and THF (0.08 mL), followed by the addition of 1.0 M aq. NaOH (0.017 mL, 0.017 mmol). The reaction mixture was stirred at room temperature for 20 min. The organic solvents and trace of water were removed under vacuum to give the crude intermediate, which was dissolved in DCM (0.044 mL), followed by the addition of TFA (0.044 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 20 min. After concentration, the residue was diluted with MeOH, filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give two mixtures of diastereoisomers of the title compound as white powders. On analytical HPLC (Waters SunFire™ C18, 2.1×50 mm, 5 μm; flow rate 3 mL/min.; injection volume 2 μL; gradient from 2 to 80% B in 3 minutes (A=water with 0.025% TFA, B=MeCN)) the diastereoisomers had the following properties:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>C(Cl)Cl.Cl>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([OH:33])[CH:35]=3)=[O:38])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: O=C(O)c1cccc(O)c1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O)c1cccc(O)c1

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, 3-hydroxybenzoic acid, and WSC-HCl was stirred in CH2Cl2 at room temperature overnight. Ethyl acetate and iN HCl were added in the reaction mixture and organic layer was separated, and washed with water and brine, and dried over magnesium sulfate, evaporated in vacuo. The colorless powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(3-hydroxyphenyl)carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [Na+].[CH3:2][S:3]([O-:5])=[O:4].N1C=CC=CC=1.Br[C:13]([CH3:19])([CH3:18])[C:14]([NH:16][CH3:17])=[O:15].O>CN(C=O)C.CCOC(C)=O>[CH3:17][NH:16][C:14](=[O:15])[C:13]([CH3:19])([S:3]([CH3:2])(=[O:5])=[O:4])[CH3:18]
Reactant: CNC(=O)C(C)(C)Br
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a suspension of methanesulfinic acid sodium salt (310 mg, 3.04 mmol) in dry DMF (3.5 mL) was added under a nitrogen atmosphere, dry pyridine (0.5 mL) and 2-bromo-N,2-dimethylpropanamide (365 mg, 2.027 mmol). The reaction mixture was stirred at 50° C. overnight, cooled and H2O (5 mL) and EtOAc (10 mL) were added. The aqueous layer was separated and extracted twice with EtOAc (5 mL). The combined organic phase was washed with brine (20 mL) and dried over Na2SO4. The solution was concentrated in vacuo and stirred in heptane (25 mL). The solids were filtered to give the desired product (88 mg, 23%) as a white solid.
Reaction SMILES: C[Si](C)(C)Cl.BrCCBr.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](I)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl[C:25]1[C:30]([NH2:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=1>CC(N(C)C)=O.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20]([C:25]2[C:30]([NH2:31])=[CH:29][C:28]([Cl:32])=[CH:27][N:26]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: BrCCBr
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC=C(c2ncc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.7 %

Procedure:
A mixture of trimethylchlorosilane and 1,2-dibromoethane (7:5 v/v, 0.125 ml) was added dropwise (keeping the T° C. below 50° C.) to a suspension of zinc powder (422 mg) in dimethylacetamide (3 ml). The mixture was stirred 20 min at room temperature then a solution of 1-(t-butoxycarbonyl)-4-iodo-piperidine (1.62 g, prepared in 2 steps from 1-(t-butoxycarbonyl)-piperidin-4-one according to J. Org. Chem. 2004, 5120) in dimethylacetamide (3 ml) was added dropwise over 5 min (slightly exothermic). The resulting mixture was stirred at room temperature for 30 min then cannulated into a mixture of 2,5-dichloro-3-aminopyridine (603 mg), copper(I) iodide (42 mg) and PdCl2(dppf) (91 mg) in dimethylacetamide (5 ml). The resulting mixture was stirred at 80° C. for 3 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (ethyl acetate:cyclohexane 3:7) to afford 3-amino-5-chloro-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (535 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) 1.4 (s, 9H), 1.8 (m, 4H), 2.6 (m, 1H), 2.8 (m, 2H), 3.7 (br s, 2H), 4.2 (m, 2H), 6.9 (s, 1H), 7.9 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH:20]=[CH:19]3)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH3:25])[CH:20]=[CH:19]3)[N:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(ccn2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(ccn2C)c1
Yield: 77.2 %

Procedure:
This compound was prepared according to general procedure D from methyl 2-(4-methyl-6-(1-methyl-1H-indol-5-yl)-2-phenylpyrimidin-5-yl)pentanoate (0.106 g; 0.256 mmol), sodium hydroxide 10N (0.256 mL; 2.56 mmol) in methanol (2.5 mL) to afford 0.079 g (76%) of the title compound as a white solid.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH:14]([C:19]([OH:21])=[O:20])[CH2:13][CH2:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[CH2:27]([O:20][C:19]([CH:14]1[C:15]2[C:11](=[CH:10][C:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:17]([OH:18])[CH:16]=2)[CH2:12][CH2:13]1)=[O:21])[CH3:28]
Reactant: CCO
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(C(=O)O)CC2
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
Analogously to Example 3, 12 g of 5-benzoyl-6-hydroxyindane-1-carboxylic acid and ethanol containing sulphuric acid give 5-benzoyl-6-hydroxy-indane-1-carboxylic acid ethyl ester in the form of yellow platelets of melting point 83°-4° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27]Br)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:26][CH2:27][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH:22]([CH3:24])[CH3:23])[CH:16]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: CC(C)Oc1cccc(C(=O)N2CCC(CCBr)(c3ccc(C(F)(F)F)cc3)C2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(C(F)(F)F)cc3)C2)c1

Procedure:
Combine 2-[3-(4-trifluoromethyl-phenyl)-1-(3-isopropoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-bromide (8 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol), K2CO3 (36 mmol), KI (0.8 mmol), and THF/H2O (3/1, 80 mL). Heat at reflux for 72 h. Concentrate in vacuo to remove THF and extract with dichloromethane (2×50 mL). Extract the combined organic layers using water (50 mL). Dry over MgSO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph on silica gel to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 70 °C

Procedure:
A mixture of 2,3-difluoro-6-hydroxybenzaldehyde (0.93 g), (bromomethyl)benzene (1.11 g) and potassium carbonate (1.22 g) in N,N-dimethylformamide (15 mL) was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]1[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[C@@H:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH3:31]
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(Cl)cc1[C@H]1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (790 mg, 1.77 mmol, 1.0 eq.) in DCM (3 mL), 4M HCl in dioxane (7.4 mL) was added. The resulting solution was stirred at r.t. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was coevaporated with EtOH (3×). To a solution of the residue in EtOH (2 mL), conc. H2SO4 (0.18 mL) was added. The solution was stirred at r.t. for 18 hours. Water and 5% aq. NaOH soln. were added and the mixture was extracted with Et2O (3×10 mL). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo to give the desired product.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:44][C:42]=2[NH2:43])[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=3)[CH:61]=[CH:62][CH:63]=2)[N:58]=[C:57]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=2)[C:56]=1[CH3:77].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:38]1([C:41]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:44][C:42]=2[NH:43][C:55]2[C:64]3[C:59](=[C:60]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][N:66]=4)[CH:61]=[CH:62][CH:63]=3)[N:58]=[C:57]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][N:72]=3)[C:56]=2[CH3:77])[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2c(-c3ccccn3)cccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.023 g, 0.048 mmol), 2,5-dimorpholinoaniline (0.095 g, 0.36 mmol), 4-chloro-3-methyl-2,8-di(pyridin-2-yl)quinoline (0.1 g, 0.30 mmol) and Pd2dba3 (0.011 g, 0.012 mmol) in toluene (3.00 mL) was added sodium tert-butoxide (0.072 g, 0.753 mmol). The reaction mixture was heated to 120° C. and stirred for 45 min. The reaction was then cooled to rt and diluted with water (25 mL). The mixture was extracted with EtOAc (2×10 mL) and DCM (1×10 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% EtOAc in hexane) to give the desired product N-(2,5-di(4-morpholinyl)phenyl)-3-methyl-2,8-di(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (1H, d, J=4.1 Hz), 8.69 (1H, m), 8.30 (1H, m), 8.20 (1H, m), 7.96 (2H, m), 7.80 (2H, m), 7.59 (1H, dd, J=8.3, 7.3 Hz), 7.32 (2H, m), 7.10 (1H, m), 6.43 (1H, m), 6.03 (1H, br. s), 3.92 (4H, br. s), 3.71 (4H, br. s), 3.08 (4H, br. s), 2.91 (4H, br. s), 2.53 (3H, s). Mass Spectrum (ESI) m/e=559.3 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][O:8]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.Cl>O1CCOCC1.O>[OH:8][CH2:7][C@H:4]1[CH2:5][CH2:6][C:2](=[O:1])[N:3]1[C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:37])[F:38])[CH:29]=1
Reactant: N#Cc1ccc(N2C(=O)CC[C@@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(N2C(=O)CC[C@@H]2CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of (R)-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoro methyl)benzonitrile 1d (3 g, 5.69 mmol) in 1,4-dioxane (30 mL), cooled to 0° C., 2M HCl in dioxane (30 mL) was added. The reaction mixture was then warmed up to room temperature and stirred for 16 h. After completion (by TLC), the reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the alcohol 1e (1.6 g, 93%) as a white solid.
Reaction SMILES: [CH3:1]I.[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1.O>CN(C=O)C>[Br:3][C:4]1[C:9]([O:10][CH3:1])=[CH:8][CH:7]=[C:6]([I:11])[N:5]=1
Reactant: Oc1ccc(I)nc1Br
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1Br
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Add K2CO2 (6.22 g, 45.1 mmol) and methyl iodide (24.6 g, 10.77 mL, 173.3 mmol) to 2-bromo-6-iodopyridin-3-ol, 2 (14.9 g, 49.5 mmol), dissolved in DMF (30 mL). Heat the reaction medium at 100° C. for 2 h, then leave it to cool to room temperature. Then stop the reaction with H2O and stir it for a further 30 min. The precipitate is then filtered, washed with H2O and dried in air to give 3 (15.7 g, 100%) in solid form, light brown: 1H NMR (CDCl3) δ 7.61 (d, 1H, J=8.4 Hz), 6.86 (d, 1H, J=8.4 Hz), 3.93 (s, 3H); m/z obs.=314 (M+1), 315.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:12]1=[O:32].[OH-].[Na+]>CO>[O:32]=[C:12]1[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][N:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:33])=[O:2]
Reactant: COC(=O)CCCCCCCn1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCCCn1cc(-c2ccccc2)n(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
The product is produced as described in example 18 from 6.9 g of 8-[2-oxo-4-phenyl-3-(3-trifluoromethyl-phenyl)-4-imidazolin-1-yl] caprylic acid methyl ester and 0.66 g of NaOH in 30 cc. of methanol. Further purification by chromatography on silicic acid gel using chloroform as eluant.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.C1(P(=[CH:32][C:33]([O:35][CH3:36])=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc2ccccc2c1
Yield: 88.2 %

Procedure:
A mixture of 2-naphthaldehyde (6.00 g) and methyl (triphenyl-phosphoranylidene)acetate (13.0 g) in toluene (100 ml) was refluxed for 14 hours. After removal of the solvent, the residue was chromatographed on silica gel (hexane:ethyl acetate:CH2Cl2=4:1:4) followed by recrystallization from hexane-cyclohexane to give the titled compound (7.19 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:10]=[N:11][CH:12]=1.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][NH2:16])[CH:10]=[N:11][CH:12]=1
Reactant: CN1CCC[C@H]1c1cncc(OCCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC[C@H]1c1cncc(OCCN)c1
Yield: 84.9 %

Procedure:
Preparation 12a: (S)-tert-butyl 2-(5-(1-Methylpyrrolidin-2-yl)pyridin-3-yloxy)ethylcarbamate (preparation 11) (105 mg, 0.33 mmol) was stirred in trifluoroacetic acid (1 mL) and DCM (5 mL) for 1.5 h. The reaction mixture was evaporated, then co-evaporated with DCM (×5) and 20% ammonia in MeOH. The crude product was purified by flash chromatography (5% [20% ammonia in MeOH] in DCM) to give the title compound as a yellow oil (62 mg, 85%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)=[O:17].O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)(=[O:9])=[O:17]
Reactant: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
1.0 g of m-chloroperbenzoic acid (purity: 70%, 4.1 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.8 mmoles) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction. the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 75.0%) of 3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 64 to 65° C.).