Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CCOCC>COCCOCCOC>[Cl:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1cccc(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: CCOC(=O)c1ccc(F)cc1Oc1cccc(Cl)c1

Procedure:
Ethyl 2,4-difluorobenzoate (6.0 g), K3PO4 (7.5 g) and 3-chlorophenol (4.1 g) were stirred at 110° C. in diglyme (25 mL) for 24 hours. The mixture was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and with brine, and dried. The solution was then concentrated. The concentrate was chromatographed on silica gel with 10% ethyl acetate/hexanes.
Reaction SMILES: [ClH:1].[C:2]1([O:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14](O)(O)[CH2:13][CH2:12]1.Cl>CC(O)C>[ClH:1].[CH2:12]1[C:13]2[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:8][C:14]=2[CH2:15][CH2:16][NH:11]1
Reactant: OC1(O)CCNCC1
Reactant: NOc1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: c1ccc2c3c(oc2c1)CCNC3
Temperature: 20 °C
Yield: 64.1 %

Procedure:
A mixture of O-phenylhydroxylamine hydrochloride (1:1) (0.625 mol) and 4,4-piperidinediol hydrochloride (1:1) (0.682 mol) in 2-propanol (615 ml) was stirred at 20° C. HCl (353 ml) was added dropwise at 20 ° C. The reaction mixture was gently heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours, then cooled to room temperature. The precipitate was filtered off, washed with diisopropyl ether, and dried. This fraction was crystallized from water (1600 ml). The desired compound was allowed to crystallize out while stirring. The precipitate was filtered off, washed with 2-propanol and diisopropyl ether, then dried, yielding 84 g (64%) of 1,2,3,4-tetrahydrobenzo-furo[3,2-c]pyridine hydrochloride (1:1) (interm. 1).
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:23]([O-])=O)[CH:20]=2)[CH2:15]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)[CH3:1])[CH2:22]2
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(CCc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[N-methyl-N-(4-nitrophenethyl)amino]-5-nitroindane (0.5 g) in ethyl acetate/methanol (40 ml/10 ml) containing 5% Pd/C (0.05 g) was stirred under a hydrogen atmosphere [206.8 kPa (30 psi)] for 4 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to give a gum which was triturated with ether. The ether was decanted and evaporated to dryness in vacuo to give the title compound, yield 0.33 g. A small sample was taken and recrystallised from diisopropyl ether, m.p. 112°-114°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[I-].[K+].[CH3:12][CH:13]([CH3:16])[CH2:14]O.ClCCl>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH:4][CH2:12][CH:13]([CH3:16])[CH3:14]
Reactant: CC(C)CO
Reactant: Nc1c(F)cccc1F
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1c(F)cccc1F
Temperature: 190 °C
Yield: 14.4 %

Procedure:
2,6-difluoroaniline (387 mg, 3 mmol), potassium iodide (996 mg, 6.00 mmol) and [Cp*IrCl2]2 (33.1 mg, 0.030 mmol) were dissolved in 2-methyl-1-propanol (3 mL, 32.4 mmol). The resulting mixture was heated by microwaves to 190° C. for 8 hours. To the reaction mixture was added dichloromethane (10 mL) and water (10 mL) and the organic phase separated (hydrophobic frit). Diethyl ether was added and the solution filtered through a silica cartridge (10 g) eluting with further diethyl ether. The filtrate was evaporated in vacuo, then purified by flash silica (Si) chromatography (using a 0-100% dichloromethane-cyclohexane gradient). The appropriate fractions were combined and concentrated to give the title product (80 mg) as a colourless oil. LCMS (M+1) 186, RT 1.26 mins.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([OH:12])=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[P:19](=[S:25])(Cl)([O:22][CH3:23])[O:20][CH3:21]>C(#N)C.CN(C)C1C=CN=CC=1>[P:19](=[S:25])([O:12][C:9]1[N:10]=[CH:11][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)([O:22][CH3:23])[O:20][CH3:21]
Reactant: COP(=S)(Cl)OC
Reactant: Oc1ncn(-c2ccccn2)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COP(=S)(OC)Oc1ncn(-c2ccccn2)n1
Reaction time: 2 h

Procedure:
A mixture of 8.10 g (0.05 m) of 1-(2-pyridinyl)-1H-1,2,4-triazol-3-ol and 8.29 g (0.06 m) of powdered potassium carbonate in 150 ml of acetonitrile was vigorously stirred together for 21/2 hours at 40°-50° C. To this mixture was successively added a solution of 0.29 g (0.0024 m (5 mole percent)) of 4-dimethylaminopyridine in 25 ml of acetonitrile followed by a solution of 7.94 g (0.048 m) of O,O-dimethyl phosphorochloridothioate in 25 ml of acetonitrile. After a 2 hour period, the reaction was complete and the reaction mixture was filtered and evaporated to dryness. The oil which remained as a residue was triturated with hexane and solidification occurred. The solid, crude O,O-dimethyl O-(1-(2-pyridinyl)-1H-1,2,4-triazol-3-yl) phosphorothioate product was recovered in a yield of 11.3 g (82 percent of theoretical) and melted at 88°-91° C. The product after recrystallization from methyl cyclohexane melted at 95°-96° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 37.68, 3.91 and 19.51 percent, respectively, as compared with the theoretical contents of 37.76, 3.87 and 19.58 percent, respectively, as calculated for the named compound. (Compound 6).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[CH:10][C:11]([CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO>[C:19]([O:18][C:16]([NH:15][CH2:14][C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][CH:12]=1)[C:3]([OH:23])=[O:2])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
The compound (76.4 mg) obtained in Example 129-3 was dissolved in methanol (4.5 ml). A 1 mol/l sodium hydroxide aqueous solution (2.3 ml) was dropped in this solution. Then, the solution was stirred at room temperature for 2 hours and then neutralized with the addition of 1 mol/l hydrochloric acid (2.3 ml). The residue obtained by distilling the solvent off was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (65.3 mg) as a pale-yellow oily substance.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6]#[N:7].Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[C:6](=[N:15][OH:16])[NH2:7]
Reactant: NO
Reactant: N#Cc1c(F)cccc1OC(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1c(F)cccc1OC(F)F
Temperature: 75 °C
Reaction time: 20 h

Procedure:
A mixture of 6.4 g of 2-difluoromethoxy-6-fluorobenzonitrile and 3.1 g of hydroxylamine hydrochloride, 2.6 g of sodium carbonate, 7 ml of water and 35 ml of ethanol was stirred for 20 hours at 75° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([O:10]C)[CH:9]=1)([O-:3])=[O:2].Cl.N1C=CC=CC=1.Cl>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:13])([F:14])[F:15])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cc([N+](=O)[O-])ccc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Temperature: 210 °C

Procedure:
5-Nitro-2-trifluoromethylanisole (10.7 g, 48.5 mmol) and pyridine hydrochloride (44.9 g, 388 mmol) were combined in a round-bottom flask and heated at 210° C. for 2 h. The reaction was cooled to RT and dissolved into 6 N HCl and EtOAc. The layers were separated, and the organic layer was washed 4× with 2 N HCl and once with brine, dried over Na2SO4, filtered, and concentrated in vacuo, to yield the title compound as a dark red solid.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([OH:27])=O)[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:32][C:30](=[O:31])[C@@H:29]([NH:28][C:25](=[O:27])[C:7]1[CH:6]=[C:5]([C@H:2]([OH:1])[CH2:3][OH:4])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=1)[CH2:33][CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[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)C[C@H](NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-amino-4-methylpentanamide (0.074 g, 0.44 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.201 g, 0.53 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 25-75% acetone in hexanes. The product fractions were isolated and evaporated in vacuo. The residue was triturated with 5 mL 50% EtOAc/hexanes, filtered and rinsed with additional 50% EtOAc/hexanes. The solid was dried under vacuum at 50° C. to yield N—((S)-1-amino-4-methyl-1-oxopentan-2-yl)-4-((S)-1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamide (compound 63) as an off-white powder (0.105 g, 0.22 mmol, 50% yield, LC/MS: m/z=482.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 8.64 (d, J=9.2 Hz, 1H), 8.20 (d, J=8.4 Hz, 2H), 8.05 (s, 1H), 8.00 (s, 1H), 7.62 (s, 1H), 7.32-7.24 (m, 2H), 7.21-7.11 (m, 5H), 5.63 (d, J=4.8 Hz, 1H), 4.88-4.82 (m, 1H), 4.76-4.69 (m, 1H), 4.62-4.53 (m, 1H), 3.63-3.49 (m, 2H), 1.76-1.56 (m, 3H), 0.96-0.89 (m, 6H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@@H:10]([NH:49][C:50](OCC1C=CC=CC=1)=[O:51])[C:11]([N:13]([CH:23]([C:41]1[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=1)[C:24](=[O:40])[NH:25][C:26]1C=C[CH:29]=[CH:28][C:27]=1OCC1C=CC=CC=1)[C@@H:14](C(OC)=O)[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12].[C:60]([OH:63])(=O)[CH3:61]>C(O)C.[Pd]>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[C@H:10]1[NH:49][C:50](=[O:51])[C@@H:14]([C@@H:15]([CH3:16])[CH2:17][CH3:18])[N:13]([CH:23]([C:41]2[C:42]([CH3:48])=[N:43][C:44]([CH3:47])=[CH:45][CH:46]=2)[C:24]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:61][C:60]=2[OH:63])=[O:40])[C:11]1=[O:12]
Reactant: CC[C@H](C)[C@H](C(=O)OC)N(C(=O)[C@H](NC(=O)OCc1ccccc1)C1Cc2ccccc2C1)C(C(=O)Nc1ccccc1OCc1ccccc1)c1ccc(C)nc1C
Reactant: CC(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C

Procedure:
The crude methyl N-[(2R)-2-(2,3-dihydro-1H-inden-2-yl)-2-({[(phenylmethyl)oxy]carbonyl}amino)acetyl]-N-[1-(2,6-dimethyl-3-pyridinyl)-2-oxo-2-({2-[(phenylmethyl)oxy]phenyl}amino)ethyl]-D-alloisoleucinate (intermediate 1) (7.46 g) was dissolved in ethanol (150 mL) and acetic acid (10 mL) and the mixture was hydrogenated at 1 atmosphere of H2 over 10% palladium on carbon (Degussa type) (1.8 g wetted with water 1:1 w:w) for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water with saturated aqueous sodium hydrogen carbonate added until the aqueous phase was basic (pH 8). The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate:water 3:1 (100 mL) then with saturated brine before being dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The crude product was purified on a Redisep silica column (120 g) eluted with 0-10% methanol in ethyl acetate to give the title compound as a pair of diastereomers (2.94 g).
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CCCC[SnH](CCCC)CCCC.[C:22](#[N:25])[CH:23]=[CH2:24].CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[CH:2]1([CH2:24][CH2:23][C:22]#[N:25])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C=CC#N
Reactant: BrC1CCCCCC1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#CCCC1CCCCCC1

Procedure:
3-Cycloheptylpropionitrile is prepared in this example according to the procedure of Example 1 using a solution of 2-bromocycloheptane (25.57 g; 144.38 mmole); Bu3SnH (50.42 g; 173.26 mmole), acrylonitrile (15.32 g; 288.77 mmole), and AIBN (1.13 g) in toluene (300 ml). Yield is 16 g; mp oil.
Reaction SMILES: C[O-].[Na+].[CH2:4]([O:11][CH2:12][C@H:13]1[C@@H:18]([S:19]C(=O)C)[CH2:17][CH2:16][CH2:15][O:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS(O)(=O)=O.O>CO>[CH2:4]([O:11][CH2:12][C@H:13]1[C@@H:18]([SH:19])[CH2:17][CH2:16][CH2:15][O:14]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)S[C@H]1CCCO[C@H]1COCc1ccccc1
Agent: CS(=O)(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: S[C@H]1CCCO[C@H]1COCc1ccccc1
Reaction time: 2 h

Procedure:
1.04 ml of a methanolic solution containing about 28% w/w of sodium methoxide was added dropwise at -10° C. to a solution of 1.422 g of dl-cis-2-benzyloxymethyl-3-acetylthiotetrahydropyran (prepared as described in Preparation 15) in 30 ml of methanol. The reaction mixture was stirred at between -10° and 0° C. for 2 hours, after which 0.33 ml of methanesulfonic acid was added. The reaction mixture was then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated by evaporation under reduced pressure. The oily residue thus obtained was subjected to column chromatography through 30 g of silica gel. The fraction eluted with mixtures of diethyl ether and hexane ranging from 3:97 to 5:95 by volume was collected to give 1.146 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][CH:10]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:26])[CH:9]=1.[H][H]>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:9][CH:10]([N:16]2[C:17](=[O:26])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]2=[O:25])[CH2:11][C:12]([CH3:15])([CH3:14])[CH2:13]1
Reactant: CC1(C)CC(c2ccncc2N)=CC(N2C(=O)c3ccccc3C2=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccncc2N)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 45 °C
Yield: 53 %

Procedure:
A solution of 2-(3-(3-aminopyridin-4-yl)-5,5-dimethylcyclohex-2-enyl)isoindoline-1,3-dione (1.0 eq) in acetic acid (0.1M) was purged with nitrogen for 10 min. Then 10% Pd/C (0.1 eq) was added. The reaction mixture was stirred at 45° C., 300 psi hydrogen atmosphere in a steel bomb overnight and at 65° C., 300 psi for 5 hours. Solids were removed by filtration over celite, then rinsed with EtOAc and MeOH. The filtrate was concentrated, diluted with EtOAc and washed 2× with sat. aq. 2M Na2CO3. The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione (53%). LC/MS (m/z): MH+=350.3, Rt=0.78. The enantiomerically pure 2-((1R,5R)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione and 2-((1S,5S)-5-(3-aminopyridin-4-yl)-3,3-dimethylcyclohexyl)isoindoline-1,3-dione were resolved by chiral HPLC (For analysis Rt=7.526 min and 13.105 min respectively; hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H 100×4.6 mm at 1 mL/min. For preparative separation, hexanes:ethanol=80:20 (v:v), Chiralcel OJ-H (250×20 mm at 20 mL/min). 1H NMR (CDCl3): δ 8.04 (s, 1H), 8.00 (d, 1H), 7.82 (m, 2H), 7.71 (m, 2H), 7.06 (d, 1H), 4.54 (m, 1H), 3.71 (m, 2H), 2.89 (m, 1H), 2.23-2.44 (m, 2H), 1.90 (m, 1H), 1.20-1.60 (m, 3H), 1.18 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6]/[C:7](=[CH:10]\[C:11](OCC)=[O:12])/[CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:18][NH2:19]>CO>[F:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6]/[C:7](=[CH:10]\[C:11]([NH:19][CH3:18])=[O:12])/[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CN
Reactant: CCOC(=O)/C=C1/COc2cc(F)ccc2N1
Solvent: CO
Product: CNC(=O)/C=C1/COc2cc(F)ccc2N1
Temperature: 35 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
A mixture of ethyl (2Z)-(7-fluoro-2H-1,4-benzoxazin-3(4H)-ylidene)acetate (Intermediate 11, 2.0 g; 8.4 mmol), MeOH (6.0 mL) and methylamine (7.3 mL of a 40 wt % aq. Solution, 84.3 mmol) was heated on a metal hotplate to 35° C. (block temperature) and stirred for 16 h. A dark brown cloudy solution was obtained. LCMS analysis indicated consumption of starting material and formation of product. The mixture was partitioned between DCM (80 mL) and water (80 mL). The organic phase was separated, then concentrated in vacuo and the residue purified by column chromatography on a 40 g silicycle silica cartridge eluting with 0-10% EtOAc: DCM, to obtain the title compound (1.10 g, 58.9%) of an orange crystalline solid that darkened on standing.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([O:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[N:4]=[C:5]2[N:6]([CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: Cn1c(=O)c2c(Cl)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cn1c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 150 °C
Yield: 67.3 %

Procedure:
3-chloro-5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (30 mg, 0.069 mmol), potassium carbonate (29 mg, 0.2 mmol) and phenol (20 mg, 0.20 mmol) are placed in a Biotage microwave vial, and then 0.3 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 23 mg of pure product as pale yellow solids. MS (ESI) m/z 496.2 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([C:16]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][NH2:22])[CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>C(#N)C>[CH2:11]([C:16]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][NH:22][C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCc1ccc(OCCCN)c(CCCCC)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCc1ccc(OCCCNC(=O)Oc2ccccc2)c(CCCCC)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
78.3 g (0.5 mol) of phenyl chloroformate was dissolved in 250 ml of acetonitrile. A mixed solution of 137 g (0.45 mol) of 3-(2,4-diamylphenoxy)propylamine, 69.5 ml of triethylamine and 250 ml of acetonitrile was added dropwise to the solution thus formed in about 3 hours with stirring while the latter was cooled with ice at a temperature of 0° C. After the dropwise addition was finished, the reaction temperature was raised to 25° C. 2 l of ice water was added to the admixture. The admixture was then extracted with chloroform. The chloroform was removed under reduced pressure. Methanol was added to the residual oily matter to obtain 150 g of 3-(2,4-diamylphenoxy)-1-phenoxycarbonylaminopropane.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=O)(C)(C)C.[Br:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](I)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].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>[Br:20][C:21]1[CH:26]=[C:25]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:24]=[N:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Reactant: Brc1cncc(I)c1
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: O
Product: Brc1cncc(-c2cc3ccccc3[nH]2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A flask containing 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (2 g, 7.66 mmol), 3-bromo-5-iodopyridine (1.45 g, 5.11 mmol), 2M K2CO3 in water (5.11 mL, 10.21 mmol), PS—Pd(PPh3)4 (2.84 g, 0.255 mmol) is flushed with N2 and dioxane (50 mL) is added. The mixture is stirred at 60° C. for 3 h, whereupon another portion of 3-bromo-5-iodopyridine (300 mg, 1.06 mmol) is added. The mixture is stirred at 60° C. overnight. The mixture is cooled to room temperature and silica gel (20 g) is added. The suspension is concentrated in vacuo and the residue is placed under high vacuum at 60° C. over the weekend. The mixture is purified by silica chromatography eluting with a 1:9 to 7:3 EtOAc-heptane gradient to give 2-(5-bromopyridin-3-yl)-1H-indole. MS (ESI) m/z 273.0, 275.1 (M+H)+.