Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.[O:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([N:10]1[C:18]2[C:13](=CC(C=C)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8].O.O.C[N+]([O-])(C)C.Cl>C1COCC1.O>[C:7]([N:10]1[C:18]2[C:13](=[CH:3][C:4]([CH2:5][CH2:6][OH:2])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: C=Cc1ccc2c(c1)CCN2C(C)=O
Reactant: C1CCOC1
Agent: B
Agent: C[N+](C)(C)[O-]
Agent: Cl
Solvent: O
Product: CC(=O)N1CCc2cc(CCO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
Borane-tetrahydrofuran complex (1.0M in THF, 20 ml, 20 mmol) was added dropwise to an ice cooled solution of 1-acetyl-2,3-dihydro-5-ethenyl-1H-indole (5.61 g, 30 mmol) in THF (150 ml). The mixture was stirred at 0° C. for 30 minute then at room temperature for 1 hr. Trimethylamine N-oxide dihydrate (8.88 g, 80 mmol) was added and the mixture was heated under reflux for 3 hr, cooled and poured into water (400 ml) and aqueous HCl (6N, 10 ml). The mixture was extracted with dichloromethane (3×400 ml) and the combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate, to give the alcohol as a white solid (3.41 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(#N)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:10][C:5]1[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Cl:1])=[CH:3][C:4]=1[CH:11]([OH:15])[CH:12]([CH3:13])[CH3:14])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(O)c(C(O)C(C)C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1cc(OC)c(Cl)cc1C(O)C(C)C
Temperature: 25 °C

Procedure:
To a solution of the above prepared 4-chloro-2-(1-hydroxy-2-methyl-propyl)-5-methoxy-phenol (1.080 g, 4.68 mmol) in 15 mL acetonitrile were successively added Cs2CO3 (1.98 g, 1.3 eq.) and ethyl bromoacetate (0.596 mL, 1.15 eq.) and the mixture vigorously stirred at ambient temperature over night. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left 1.57 g of the title compound as light brown oil, used directly for the next step.
Reaction SMILES: [H-].[Na+].[Cl-].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][C:7]=1[CH3:32].[O:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1[O:39][CH2:40][C:41]1[N:42]=[C:43]([C:48]2[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=2)[S:44][C:45]=1[CH:46]=O>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9](/[CH:10]=[CH:46]/[C:45]2[S:44][C:43]([C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:56])([F:57])[F:55])=[CH:50][CH:49]=3)=[N:42][C:41]=2[CH2:40][O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:8][C:7]=1[CH3:32]
Reactant: O=Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1COC1CCCCO1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 242mg, 6.32mmoles, 1.4eq) in dry CH2Cl2(15ml) was added (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62g, 6.32mmoles, 1.4eq). This was allowed to stir at room temperature for 1.5hours followed by the dropwise addition of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (1.68g, 4.51mmoles, 1eq) in anhydrous carbon tetrachloride (25ml). The resulting reaction mixture was refluxed overnight at which point (after cooling to room temperature) the reaction washed with 1N NaOH, H2O, brine, dried over Na2SO4and concentrated in vacuo to yield a >100% yield of a light green oil. The crude material was used without purification.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:17][C:18]1[N:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([OH:28])[N:19]=1.C(N(CC)CC)C>C(O)C>[NH2:17][C:18]1[N:19]=[C:20]([OH:28])[C:21]([N+:25]([O-:27])=[O:26])=[C:22]([NH:2][C:3]([CH3:16])([CH3:15])[C:4](=[N:13][OH:14])[CH2:5][O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:23]=1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)(N)C(COc1ccccc1)=NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(Nc1nc(N)nc(O)c1[N+](=O)[O-])C(COc1ccccc1)=NO
Yield: 16.1 %

Procedure:
A mixture of 3-amino-1-(p-chloro)-phenoxy-3-methylbutan-2-one oxime hydrochloride (IV) (5.58 g), 2-amino-4-chloro-6-hydroxy-5-nitropyrimidine (III) (Hal = Cl) (3.81 g) and dry triethylamine (8.2 g) was heated to reflux in dry ethanol (240 ml) for 16 hours and filtered hot. The filtrate was reduced in volume and the solid so obtained was filtered off. Recrystallisation from ethanol gave the nitropyrimidine oxime (II) (1.17 g) as a pale yellow gelatinous solid, m.p. >250°C (decomp.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]CCCC.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[C:35]=1[CH:36]=[O:37]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:36]([OH:37])[C:35]1[C:38]([O:42][CH3:43])=[CH:39][CH:40]=[CH:41][C:34]=1[O:33][CH3:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: COc1cccc(OC)c1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2c(OC)cccc2OC)sc2ncccc12
Yield: 63.6 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyeth-oxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.35 mmoles) [Example 4(A)], THF (5 ml), n-BuLi (2.5M, 0.16 ml, 0.41 mmoles) and 2,6-dimethoxybenzaldehyde (88 mg, 0.53 mmoles). Flash chromatography (50% EtOAc/hexanes) provided 0.13 g (62%) of the title compound as a pink oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10])=O.O.[NH2:22][NH2:23]>CCO>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:9](=[O:10])[NH:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2)c(C(=O)O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc2c(-c3cccc(F)c3)n[nH]c(=O)c2c1
Yield: 34.8 %

Procedure:
A solution of 2-(3-fluorobenzoyl)-5-methoxybenzoic acid (21 g, 76.5 mmol) in hydrazine hydrate (4.09 mL, 84.0 mmol) and EtOH (300 mL) was heated overnight at 80° C. The reaction mixture was concentrated, diluted with water (300 mL), and the precipitate was filtered and dried to yield 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.2 g). (270.85 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 3.96 (s, 3H), 7.36-7.43 (m, 3H), 7.46-7.49 (m, 1H), 7.57-7.64 (m, 2H), 7.73-7.73 (d, J=2.8, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1.C(N(CC)CC)C.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[N:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cc1cc(Cl)nc(Cl)n1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cc1cc(N2CCOCC2)nc(Cl)n1)c1ccccc1
Temperature: -5 °C
Yield: 57.1 %

Procedure:
2,4-dichloro-6-[(phenylsulfonyl)methyl]pyrimidine (6 g, 19.8 mmol) was dissolved in DCM (50 mL) and stirred (under nitrogen) at −5° C. Triethylamine (3.06 mL, 21.8 mmol) was added to give a clear brown solution. Morpholine (1.65 mL, 19.8 mmol) was dissolved in DCM and added dropwise keeping the reaction below −5° C. The cooling bath was then removed and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was then washed with water (50 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was chromatographed on silica, eluting with 0-50% ethyl acetate in DCM to give the desired material as a white solid (4 g).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:4])[CH:2]=[CH2:3].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[CH:18]=1.N12CCN(CC1)CC2>>[OH:24][CH:23]([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[C:2](=[CH2:3])[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)=[O:4]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OCc1cccc(C(F)(F)F)c1
Agent: C1CN2CCN1CC2
Product: C=C(C(=O)OCc1cccc(C(F)(F)F)c1)C(O)c1cccnc1
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 62 mg (0.27 mmol) of 3-(trifluoromethyl)phenylmethyl acrylate, 29 mg (0.27 mmol) of pyridine-3-carboxaldehyde, and 30 mg (0.27 mmol) of 1,4-diazabicyclo [2.2.2]octane (DABCO) was thoroughly shaken on a Vortex mixer, and then stored at 0° C. overnight. The product was purified by preparative HPLC (prep HPLC) using a Gilson 210 HPLC/fraction handler to give 47 mg (0.14 mmol; 52% yield) of the desired Baylis-Hillman adduct, 3-(trifluoromethyl)phenylmethyl β-hydroxy-α-methylene-3-pyridinepropanoate. 1H NMR (CDCl3): δ 5.18 (s, 2H), 5.63 (1H), 5.98 (1H), 6.45 (1H), 7.70 (d of t, 1H), 8.49 (d of d, 1H), and 8.56 ppm (d, 1H). MS m/z: 338.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[C:8]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([O:21]C)=[O:20])[C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[S:4][CH:3]=1.[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:26])=[C:8]([CH:18]([CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20])[C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[S:4][CH:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2scc(C)c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a solution of methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.087 g; 0.237 mmol) in methanol (5 mL) and ethanol (2.6 mL) was added a 5% sodium hydroxide solution (6.8 mL; 8.500 mmol). The reaction mixture was heated under reflux for 5 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.052 g (62%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.NC1C=CC=CC=1N.C(=O)C1C(=CC=CC=1)[OH:35]>[Co].N1C=CC=CC=1>[C:14]1([P:7](=[O:35])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccccc1O
Agent: [Co]
Agent: Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
81.7 mg. (0.164 mmol) of cobalt (saloph) pyridine nitro complex and 187 mg. (0.713 mmol) of triphenylphosphine were dissolved in 20 ml. of 1,2-dichloroethane together with 0.5 ml. of pyridine. (The saloph ligand is the tetradentate ligand [1,2-(ortho-OC6H4CH=N)2C6H4 ]2- obtained by condensation reaction of o-diaminobenzene with salicylaldehyde). The resulting solution was stirred under an oxygen atmosphere for 18 hours at 60° C. The resulting reaction product was analyzed by infrared spectroscopy showing a quantitative yield of triphenylphosphine oxide, i.e. 0.713 mmol. This example is illustrative of catalytic oxidation by a cobalt nitro complex having a tetradentate ligand and a monodentate basic ligand in accordance with this invention.
Reaction SMILES: C1(C2CCCCCCCC2)BCCCCCCC1.[Cl:19][CH2:20][CH2:21][CH2:22][C:23]#[CH:24].NO.[CH2:27]([Zn:29]CC)[CH3:28].CCCCCC>C1COCC1>[CH2:27]([Zn:29][CH:24]=[CH:23][CH2:22][CH2:21][CH2:20][Cl:19])[CH3:28]
Reactant: C#CCCCCl
Reactant: CC[Zn]CC
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: NO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC[Zn]C=CCCCCl
Reaction time: 1 h

Procedure:
A solution of 9-borabicyclononane (0.24 g, 2.0 mmol) in THF (5 mL) was added dropwise to a solution of 5-chloro-1-pentyne (0.21 g, 2.0 mmol) in THF (5 mL). After 1 h, the solvent was removed at reduced pressure. The resultant vinyl boron derivative was dissolved in toluene (5 mL) and aminoalcohol 1 (0.05 g, 0.17 mmol) prepared as in Example 1 was added. Then 1 M diethylzinc in hexane (3 mL, 3 mmol) was added via syringe at −78° C., forming ethyl-(5-chloro-1-pentenyl)zinc in situ. The dry ice bath was replaced with a wet ice bath and immediately a solution of isobutyraldehyde (0.17 g, 2.4 mmol) in hexane (5 mL) was added dropwise. After 1 hour the wet ice bath was removed and the mixture was stirred at room temperature for 8 h. Acetic anhydride (500 μL) was added and the mixture was allowed to stand overnight. GC analysis at 130° C. on Cyclodex B revealed that trans-3-acetoxy-2-methyl-8-chlorooct-4-ene had been formed in 92% enantiomeric excess.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:41][C:42]1([CH3:50])[CH2:48][C:47](=[O:49])[O:46][C:44](=[O:45])[CH2:43]1.C(=O)([O-])O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:47](=[O:49])[CH2:48][C:42]([CH3:50])([CH3:41])[CH2:43][C:44]([OH:46])=[O:45])[CH2:11][CH:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CC(C)(C)CC(=O)O)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
To a mixture of 181 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(3-phenylpiperidin-4-yl)methyl]carbamate, 0.114 mL of triethylamine, and 3.0 mL of THF was added 64 mg of 3,3-dimethylglutaric anhydride at room temperature, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by stirring, extracting with chloroform, and drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 266 mg of 5-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,3-dimethyl-5-oxopentanoic acid as a crude product. ESI+: 587
Reaction SMILES: Cl.[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:19][C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>C(Cl)Cl>[C:20]([O:19][C@H:12]1[C@H:13]([NH:18][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:14][C@H:15]([CH2:16][OH:17])[C@H:11]1[O:10][C:2](=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccncc1
Reaction time: 0.33 h
Yield: 60 %

Procedure:
A solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diyl dibenzoate hydrochloride (150. mg, 0.380 mmol) in DCM (10.0 mL) at 0° C. was treated with EtN (0.170 mL, 1.22 mmol) and stirred for 20 min. Isonicotinoyl chloride (88.0 mg, 0.490 mmol) was then added and the mixture was stirred for 2 h. The reaction was treated with saturated aqueous solution of ammonium chloride (50 mL) and extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0 to 10% MeOH in DCM to afford the title compound (100. mg, 60%). LC/MS: Rt=1.49 min, ES+ 461 (FA standard).
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5](B(O)O)=[CH:6][CH:7]=1)=[O:2].I[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)[N:16]([CH2:30][C:31]([NH:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:15]2=[O:37]>O1CCCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH:1]([C:3]1[O:4][C:5]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)[N:16]([CH2:30][C:31]([NH:33][CH:34]([CH3:35])[CH3:36])=[O:32])[C:15]3=[O:37])=[CH:6][CH:7]=1)=[O:2]
Reactant: COc1cccc(-c2nc3ccc(I)cc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: COc1cccc(-c2nc3ccc(-c4ccc(C=O)o4)cc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
2-formylfuran-5-boronic acid (118 mg, 0.84 mmol) (Frontier Scientific), copper (I) thiophene-2-carboxylate (136 mg, 0.72 mmol) (Frontier Scientific), and tetrakis(triphenylphosphine)palladium (75 mg, 10 mol %) were added to a solution of 2-[6-iodo-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.24) in tetrahydrofuran (10 mL) under Argon. The solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo. The resulting oil was purified by chromatography on a silica gel with methanol:dichloromethane (1:19, v/v) as eluent to give 2-[6-(5-formylfuran-2-yl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (90 mg, 0.20 mmol, 31%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl-:8].[K+].[Pt+2:10].[Cl-:11].[Cl-]>O>[Pt+2:10].[Cl:8][C@H:3]1[C@@H:2]([NH2:1])[CH2:7][CH2:6][CH2:5][N:4]1[Cl:11]
Reactant: [Cl-]
Reactant: NC1CCCNC1
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@H]1CCCN(Cl)[C@H]1Cl
Temperature: 25 °C
Reaction time: 40 h
Yield: 69.6 %

Procedure:
To a solution of (3RS)-3-aminopiperidine (1.7 g) in water (1000 ml) is added platinum (II) potassium chloride (7.2 g) and the mixture is stirred at room temperature for 40 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added a small amount of water, and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3RS)-3-aminopiperidine platinum (II) (4.3 g) as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(Cl)c21
Yield: 53.9 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxyphenyl)-1H-indazole (0.129 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.081 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.CC1(C)C2C=[CH:37][CH:36]=[C:35](P(C3C=CC=CC=3)C3C=CC=CC=3)[C:34]=2[O:33]C2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(O)CCC>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([CH:34]([CH:35]4[CH2:37][CH2:36]4)[OH:33])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: Cl[Pd]Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(Nc1nc2c(C(O)C3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 100 °C

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.100 mmol), palladium(II) chloride (0.355 mg, 1.999 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.157 mg, 1.999 μmol), triethylamine (18.11 μl, 0.130 mmol) and 1-butanol (1000 μl) were combined in a 40 mL vial and sparged with nitrogen for 5 minutes. The cap on the vial was removed and the atmosphere changed to carbon monoxide by pressurizing to 30 psi and releasing the pressure 3 times inside a stainless steel pressure vessel. Then, the pressure of CO was adjusted to 100 psi and heated to 100° C. for 5 h. Then, the reaction was cooled to room temperature, the reaction was then poured into ethyl acetate, washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a white solid. 1H NMR (500 MHz, C2D6SO) δ 11.68 (d, 1H, J=6.0 Hz), 10.04 (d, 1H, J=2.0 Hz), 8.50 (d, 1H, J=9.0 Hz), 7.83 (d, 1H, J=7.0 Hz), 7.78 (d, 1H, J=7.5 Hz), 7.68 (d, 1H, J=8.5 Hz), 4.81 (m, 1H), 4.22 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.17 (m, 6H), 0.93 (s, 9H). LRMS (ESI) calc'd for (C23H29BrN3O3) [M+H]+ 476.1; found 476.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[O:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH:15](O)=O>>[CH3:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[CH:15][NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[O:13]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Reactant: O=CO
Product: CC(C)Cn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
A solution of 24.2 g of 5,6-diamino-1-(2-methylpropyl)-2,4-(1H,3H)-pyrimidinedione (XVI) in 60 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 17.8 g (XVII). The amide (XVII) was refluxed in 50 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from ethanol. Yield 11.6 g (46%), NMR. ##STR10##
Reaction SMILES: ClCC(O)=[O:4].[C:6]1([CH3:21])[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:14](=[O:20])[NH:15][C:16](=S)[NH:17][CH:18]=2)[CH:7]=1>Cl>[C:6]1([CH3:21])[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[C:14](=[O:20])[NH:15][C:16](=[O:4])[NH:17][CH:18]=2)[CH:7]=1
Reactant: Cc1cccc(Oc2c[nH]c(=S)[nH]c2=O)c1
Reactant: O=C(O)CCl
Agent: Cl
Product: Cc1cccc(Oc2c[nH]c(=O)[nH]c2=O)c1
Yield: 92 %

Procedure:
To a solution of 73.3 g (0.744 mol) chloroacetic acid in 700 ml 12N HCl was added 28.6 g (0.122 mol) of 5-m-tolyloxy-2-thiouracil. The slurry was heated at reflux for 35 hours and filtered while still hot. The resulting white solid was washed well with H2O and dried to give 24.5 g of 5-m-tolyloxyuracil (m.p. 291°-295°).