Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=C[C:17](C#N)=[C:16](N)[CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[N:29][CH:28]=[N:27][CH:26]=1.C(O)(=O)C>C(O)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[C:26]3[C:17]([C:30]([NH2:25])=[N:29][CH:28]=[N:27]3)=[CH:16][CH:15]=2)[C:9]1=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ncncn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc(C#N)c(N)c2)C1=O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3c(N)ncnc3c2)C1=O
Reaction time: 8 h
Yield: 520.4 %

Procedure:
[1-(3-Amino-4-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]carbamic acid tert-butyl ester (890 mg, 2.69 mmol) and 1,3,5-triazine (650 mmol, 8 mmol) are combined in ethanol (40 mL), and acetic acid (480 mg, 8 mmol) added. The reaction mixture is refluxed under nitrogen overnight, cooled and presorbed directly onto silica. The product is purified by column chromatography on silica with 5-20% methanol/dichloromethane (containing 0.5% of 28% aqueous ammonium hydroxide). The product factions are combined and concentrated, and the residue left under high vacuum overnight. The product is isolated as a pale yellow powder (0.50 g, 14 mmol).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:32])([O:29]CC)[O:26]CC)=[CH:14][N:15]3[CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[Si](C)(C)C.C(O)C>C(Cl)(Cl)Cl>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:33])[C:13](/[CH:23]=[CH:24]/[P:25](=[O:26])([OH:32])[OH:29])=[CH:14][N:15]3[CH:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:10][C:9]=2[F:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOP(=O)(/C=C/c1cn(C(CC)CC)c2cc(NC3CCCCC3)c(F)cc2c1=O)OCC
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCC(CC)n1cc(/C=C/P(=O)(O)O)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
13 g of diethyl {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonate was dissolved in 150 ml of chloroform, and 27.2 ml of bromotrimethylsilane was added, followed by overnight stirring at room temperature. Ethanol was added to the reaction mixture, followed by concentration under a reduced pressure. Aqueous 1 M sodium hydroxide solution and ether were added to the resulting residue to carry out layer separation operation. Concentrated hydrochloric acid was added to the aqueous layer, followed by stirring at room temperature for 2 hours. Then, the insoluble materials were collected by filtration and washed with water to obtain 10.32 g of {(E)-2-[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]vinyl}phosphonic acid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:17]O>CCCCCC.C(OCC)(=O)C>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: Cc1ccccc1CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1C
Yield: 98 %

Procedure:
30.0 g of o-tolylacetic acid (0.2 mol) was dissolved in 100 ml of methanol, 5 ml of concentrated sulfuric acid was added thereto and the resulting solution was stirred with heating for 6 to 12 hours. The resulting solution was cooled and the solvent was removed under a reduced pressure to obtain a residue. The residue was washed twice with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was removed under a reduced pressure. The residue thus obtained was subjected to column chromatography using a mixture of n-hexane and ethyl acetate (4:1) as an eluent to obtain 32.15 g (yield 98%) of the title compound as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[S:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[NH:16][C:17]\1=[O:18].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>O1CCCC1>[N:57]1([CH2:56][CH2:55][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3/[CH:11]=[C:12]2\[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[NH:16][C:17]\2=[O:18])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: OCCN1CCCCC1
Reactant: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccc(O)cc12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccc(OCCN3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.7 %

Procedure:
To a solution of (Z)-2[(5-hydroxyindol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (1.00 g, 3.24 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.23 g, 4.87 mmol) in dry tetrahydrofurane-(40 ml), tributylphosphine (0.98 g, 4.87 mmol) was added under nitrogen atmosphere keeping the mixture at 0–5° C. After 5 min N-(2-hydroxyethyl)piperidine (0.63 g, 4.88 mmol) was added at the same temperature. The cooling bath was removed and the mixture stirred at room temperature for 48 h. Then the solvent was removed under reduced pressure and the residue chromatographed (silica gel, eluent, ethyl acetate:ethanol (90:10) to (80:20)) to yield 0.2 g (22%) of the entitled product.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[CH3:18]
Reactant: CCOC(=O)C1CCCNC1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Temperature: 80 °C

Procedure:
A 25 mL round-bottom flask was charged with ethyl nipecotate (4.0 mL, 25.7 mmol, Aldrich) and ethyl acrylate (3.4 mL, 31.4 mmol; Aldrich). The flask was purged with nitrogen and the mixture was heated to 80° C. for 20 hours, then purified by silica gel chromatography (ethyl acetate-dichloromethane-triethylamine 50:50:1; Rf=0.28) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.23-1.28 (m, 6H), 1.42-1.59 (m, 2H), 1.68-1.74 (m, 1H), 1.89-1.95 (m, 1H), 2.01-2.08 (m, 1H), 2.17-2.24 (m, 1H), 2.46-2.56 (m, 3H), 2.68-2.76 (m, 3H), 2.94-2.99 (m, 1H), 4.09-4.17 (m, 1H); MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@H:19]2[C@@H:10]([N:11]([CH2:26][C:27]([OH:29])=O)[C:12](=[O:25])[C:13]3[C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([N:32](CC)CC)C.ClC(OCC)=O.CN>C1COCC1>[CH3:30][NH:32][C:27](=[O:29])[CH2:26][N:11]1[C@H:10]2[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:20][C@@H:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:21]([F:24])([F:22])[F:23])[C:13]=2[C:12]1=[O:25]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N(CC(=O)O)[C@H]2C1
Agent: CCOC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 2-((3aR,9bS)-2-(tert-butoxycarbonyl)-5-oxo-6-(trifluoromethyl)-1,2,3,3a-tetrahydro-5H-pyrrolo[3,4-c]isoquinolin-4(9bH)-yl)acetic acid (40 mg, 0.1 mmol) in 4 mL of THF at 0° C. was added triethylamine (0.017 mL, 0.12 mmol) and ethyl chloroformate (0.012 mL, 0.12 mmol). The reaction was allowed to stir for 30 min at 0° C. and then there was added methylamine (0.1 mL of a 2.0M solution in THF, 0.2 mmol). The resulting mixture was stirred for 1 h at 0° C. and then was quenched with 10 mL of 1N HCl. The mixture was extracted with ethyl acetate and the organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 30 mg (70%) of the title compound which was sufficiently pure to be used without purification. LRMS (ESI): 428.24 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([CH:17]=[CH2:18])=[CH:8]2.B.[OH-:20].[Na+].OO>C1COCC1.O>[OH:20][CH2:18][CH2:17][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[CH:8]=1
Reactant: [OH-]
Reactant: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2cc(CCO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5,6,7-Trimethoxy-2-vinylnaphthalene (1.215 g) was dissolved in dry THF (10 mL) under an argon atmosphere, a THF solution (4.7 mL) of 1 M borane was added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 2 hours. Water (4 mL) was added to the reaction mixture at 0° C., and an aqueous solution (1.2 mL) of 4 M sodium hydroxide was then added. 31% Aqueous hydrogen peroxide (0.5 mL) was added to the reaction mixture at 0° C., and the mixture was stirred at 50° C. for 50 minutes. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:36]3[CH2:37][C:34]([F:38])([F:33])[CH2:35]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: FC1(F)CNC1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CC(F)(F)C1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in 1,2-dichloroethane (3 mL) was added 3,3-difluoroazetidine hydrochloride (55.7 mg, 0.430 mmol) followed by sodium triacetoxyborohydride (91 mg, 0.430 mmol). After stirring overnight, the mixture was quenched with water. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C(N(CC)CC)C.[F:12][C:13]1[C:18]([C:19](Cl)=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].CC[O:28]CC>>[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[F:12][C:13]1[C:18]([C:19]([OH:28])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([F:24])[C:14]=1[F:25].[CH2:1]([NH2:4])[CH2:2][NH2:3]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CCOCC
Solvent: CCN(CC)CC
Solvent: NCCN
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1F

Procedure:
Ethylene diamine (130 mg, 2.1 mmol) and triethylamine (510 mg, 5.0 mmol), together dissolved in 10 mL anhydrous ether is added to pentafluorobenzoyl chloride (1.2 g, 5.0 mmol) in 10 mL anhydrous ether. White precipitate is obtained and filtered off. The residue is washed with chloroform, then water and then filtered to recover ethylene diamine bis(pentafluorobenzoate) (III) as white needle crystals (yield, 100%). Sodium azide (270 mg, 4.2 mmol) in 1.7 mL water and 4.0 mL DMF is then reacted with III (870 mg, 2.0 mmol) in 20 mL DMF, and stirred overnight on a 60° C. hotplate. A white precipitate is obtained. The solution is reduced to half-volume by evaporation and the precipitate is filtered off (yield, 35%), dried and recrystallised from DMF to give ethylene diamine bis(4-azido-2,3,5,6-tetrafluorobenzoate) (IV) as white crystals. FTIR: 2129 (N3 asymmetric stretch), 1666 (C═O stretch), 1554, 1483, 1242 (N3 symmetric stretch), no acid OH band at 3000-3500.
Reaction SMILES: [F:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CO.O1CCOCC1.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:1][C:2]1[C:11]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-difluoro-3-(trifluoromethylsulfonyloxy)benzoate (3.0 g, 9.4 mmol, 1.0 eq), 3-fluorophenylboronic acid (1.57 g, 11.2 mmol, 1.2 eq), K2CO3 (5.2 g, 37.6 mmol, 4.0 eq) and Pd(PPh3)4 (543 mg, 0.47 mmol, 0.05 eq) in a mixture of MeOH (10 mL) and dioxane (30 mL) was heated to 80° C. under N2 overnight. After cooling, the resulting mixture was concentrated in vacuo and purified by flash column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (1.7 g, 68%).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([C:6]([N:8]=[CH:9][N:10](C)C)=O)=[C:4]([F:16])[CH:3]=1.O.[NH2:18]N>C(O)(=O)C>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([C:6]2[N:8]=[CH:9][NH:10][N:18]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Cc1cc(C(=O)N=CN(C)C)c(F)cc1Br
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2nc[nH]n2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide (24.6 g, 86.2 mmol) in acetic acid (200 mL) was added dropwise hydrazine hydrate (25 mL, 0.70 mol) at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was filtered washed with water (500 mL×3) and dried under reduced pressure to give the title compound (15 g, 68% yield) as a white solid. MS (ESI) m/z 256.0 [M+1]+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1.C([O:16][C:17](=O)[CH2:18][CH:19]1[CH2:24][CH2:23][C:22]([N:31]([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:32][N:31]([CH3:33])[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH:19]([CH2:18][C:17]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)=[O:16])[CH2:24][CH2:23]1
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 11.9 ml; 19 mmol) was added dropwise at 0° C. to a solution of p-tolylamine (1.02 g; 9.5 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (2.5 g; 8.6 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was taken up in ether. A solid then remained (less polar diastereoisomer; 1.518 g; 50%); the supernatant was chromatographed on silica gel (eluent:ether, then ether/methanol 4:1). 142 mg (4.7%) of the less polar and 1.20 g (40%) of the more polar diastereoisomer were obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=4[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CNC(=O)CCN3C(C)=O)ncc1Cl

Procedure:
2-[2-(1-Acetyl-4-oxo-1,2,3,4,5,6-hexahydro-benzo[b][1,5]diazocin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. Isolated as a beige solid. MP: 97-103. HPLC purity: 95%, LCMS: 512.28 (M+H)HNMR: CD3OD: 8.16 (s, 1H), 7.51-7.41 (m, 5H), 7.12 (d, J=8.6 Hz, 1H), 4.79-4.75 (m, 1H), 4.37-4.33 (m, 1H), 3.86-3.79 (m, 1H), 3.20-3.12 (m, 1H), 2.86 (s, 3H), 2.73-2.71 (m, 1H), 2.49-2.44 (m, 1H), 1.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.I.C(O)(=O)C>O>[NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[O:11][C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: COc1ccc(-c2cc(=O)c3ccccc3o2)c(N)c1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(O)ccc1-c1cc(=O)c2ccccc2o1
Temperature: 110 °C
Yield: 48.9 %

Procedure:
To a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer was added 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (770 mg, 2.88 mmol), hydroiodic acid (10 mL) and acetic acid (4 mL). The reaction mixture was heated to 110° C. for 8 h. The reaction mixture was cooled to rt and diluted with water. The precipitate was filtered off, washed with water and dried to give the crude compound, which was purified by column chromatography using 2% MeOH in CH2Cl2, to give 2-(2-amino-4-hydroxy-phenyl)-chromen-4-one (357 mg, 49%). MS (ES) m/z: 254.05 (M+1), 149.00, 134.01, and 121.00.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H]2[C@H]([O:15][C:16]3[CH:17]=[C:18]([OH:34])[C:19]4[C:25](=[O:26])[CH2:24][C@@H:23]([C:27]5[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=5)[O:22][C:20]=4[CH:21]=3)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O>Cl>[CH:32]1[C:27]([C@H:23]2[O:22][C:20]3[CH:21]=[C:16]([OH:15])[CH:17]=[C:18]([OH:34])[C:19]=3[C:25](=[O:26])[CH2:24]2)=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=1
Reactant: C[C@@H]1O[C@@H](O[C@H]2[C@H](Oc3cc(O)c4c(c3)O[C@H](c3ccc(O)cc3)CC4=O)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@H](O)[C@H]1O
Agent: Cl
Product: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21
Reaction time: 3 h

Procedure:
616.5 grams naringin were added to a round bottomed flask, followed by the addition of about one liter of 0.5 N hydrochloric acid. Upon stirring and refluxing, the naringin dissolves to form a yellow to red-brown solution. While a brown gummy or oily material initially forms, it eventually disappears. As the reaction proceeds, a yellow solid precipitates. The reaction time is approximately 2 to 4 hours. The solution is cooled, and the yellow solid filtered and washed with copious amounts of water until the washings are no longer acidic. The amount of naringenin produced is about 160 grams.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([CH3:10])([O-:9])[CH3:8].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].Cl>O>[C:7]([O:9][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21])([CH3:10])([CH3:8])[CH3:6]
Reactant: CC(C)(C)[O-]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.9 %

Procedure:
A tetrahydrofuran (THF) solution (20 ml) of potassium tert-butoxide (3.55 g, 31.6 mmol) was cooled in an methanol-ice bath, and 4.2 g of 2,5-difluoronitrobenzene (26.4 mmol) was further added. The mixture was heated to room temperature, stirred for 96 hours, and further stirred at 60° C. for 1 hour. Water (2 ml) and 2N-hydrochloric acid (2 ml) were added to the reaction mixture while cooling with an ice water bath, and subsequently water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=19:1). The purified product was concentrated under reduced pressure to thereby obtain 4.5 g of oily orange 1-tert-butoxy-4-fluoro-2-nitrobenzene (yield: 80%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH2:28])=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1>>[O:17]1[C:22]2[CH:23]=[CH:24][C:25]([CH2:27][NH:28][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:5]([F:16])=[CH:4][N:3]=3)=[CH:26][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCc1ccc2c(c1)OCCO2
Product: Oc1cccc(Nc2nc(NCc3ccc4c(c3)OCCO4)ncc2F)c1

Procedure:
In a manner analogous to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-6-ylmethylamine gave N2-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3) δ 4.24 (s, 4H), 4.45 (d, J=6.0 Hz, 2H), 6.55 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 6.66 (d, 1H), 6.84 (m, 4H), 6.90 (m, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.30 (m, 1H), 7.86 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ −170.44; LCMS: ret. time: 18.33 min.; purity: 96.75%; MS (m/e): 369.03 (MH+).
Reaction SMILES: [N: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.[C:13]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:15][CH2:16][CH3:17])=[O:14]>C1COCC1>[N: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:18]/[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc2ccccc2n1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
A solution of quinoline-2-carboxaldehyde (1.51 g, 9.65 mmol) in THF (15 ml) was heated under reflux with (carbethoxymethylene) triphenylphosphorane (3.36 g). After 2 hr, the THF was removed and the residue was chromatographed using toluene/EtOAc (18:1) as eluent to afford 1.70 g of the title compound.