Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([N+:20]([O-])=O)[C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]>[Ni].O1CCCC1>[C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16]([CH3:19])=[CH:17][CH:18]=2)[NH2:20])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C)c([N+](=O)[O-])c2)ccc(C(C)=O)c1O
Agent: [Ni]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C)c(N)c2)ccc(C(C)=O)c1O

Procedure:
1.0 g of Raney nickel is added to a solution of 9.1 g (23.5 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylnitrobenzene in 90 ml of tetrahydrofuran and the whole is hydrogenated at room temperature. The catalyst is filtered off and washed with tetrahydrofuran. The filtrate is concentrated to dryness by evaporation under reduced pressure. 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-6-methylaniline is obtained having an Rf value=0.12 (silica gel/methylene chloride).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:12]Br>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:9]1[C:8]([OH:11])=[CH:7][CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:10]=1
Reactant: CC(C)(C)c1ccc(O)cn1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(O)c(Br)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-(1,1-dimethylethyl)-3-pyridinol, (3.8 g) in pyridine (150 ml) was added bromine (1.29 ml), diluted in pyridine, dropwise at 20 C. The reaction mixture was allowed to stir at 25-30 C. for 1 h. The reaction had gone to completion by tlc. It was poured into brine and extracted with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The crude material was subjected to flash chromatography using a 0-5% gradient of ethyl acetate in hexane to give the title compound, 2.9 g
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:24]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:24])[C:3](=[O:2])[N:13]([CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[C:11]=1[CH3:12])=[O:8]
Reactant: CCC(CC)CNC(C)=C(C=CC(=O)OC)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)Cn1c(C)c(C(=O)OC)cc(Br)c1=O
Temperature: 25 °C
Yield: 66.9 %

Procedure:
MeOH (240 mL) was added to a flask containing 4-[1-(2-ethyl-butylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (7.32 g, 25.9 mmol). NaOMe solution (5.9 mL, 25.9 mmol, 4.375 M in MeOH) and N-bromosuccinimide (5.52 g, 31.0 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-25% EtOAc/hexanes) to give 5.72 g of the title compound. MS: (+) m/z 352.18, 354.19 (M+Na, 7″81Br).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:5][CH:4]([CH2:15][OH:16])[O:3]1.ClCCl.[OH2:20]>C(#N)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([N:6]2[CH2:5][CH:4]([C:15]([OH:20])=[O:16])[O:3][C:2]2=[O:1])=[CH:8][CH:9]=1)#[N:12]
Reactant: N#Cc1ccc(N2CC(CO)OC2=O)cc1
Reactant: O
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1ccc(N2CC(C(=O)O)OC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1 g of 4-(2-oxo-5-hydroxymethyloxazolidin-3-yl)benzonitrile [obtainable according to EP 300 272] dissolved in 12 ml of acetonitrile is added at 16° to a solution of 3.6 g of Na dihydrogen phosphate dihydrate, 3.9 g of Na metaperiodate and 36 mg of RuCl3 in 23 ml of water/2.3 ml of dichloromethane. The reaction mixture is stirred at room temperature for 12 h, filtered and given the customary workup. Concentration by evaporation to dryness in vacuo gives 3-(4-cyanophenyl)-2-oxo-5-oxazolidinecarboxylic acid, m.p. 204°.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][N:7]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][C@H:19]3[O:28][Si](C(C)C)(C(C)C)C(C)C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:39][CH:40]([CH3:41])[CH3:42])[S:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C@@H:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:20][C@H:19]3[OH:28])=[CH:15][CH:16]=2)(=[O:9])=[O:10])=[CH:43][CH:44]=1
Reactant: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O[Si](C(C)C)(C(C)C)C(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CN(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccc(O[C@@H]2CCN(S(C)(=O)=O)C[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of N-(4-Chloro-benzyl)-N-isobutyl-4-((+/−)trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy)-benzenesulfonamide (271 mg) in THF (5 mL) was added a 1 M solution of tetrabutylammonium fluoride in THF (609 μL, 609 mmol) and the reaction was stirred at room temperature for 30 minutes. Water was added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated, purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) and freeze dried to give the title compound (107 mg). 1H NMR (400 MHz, DMSO): δ 7.76 (d, 2H), 7.36-7.37 (m, 4H), 7.20 (d, 2H), 5.54 (d, 1H), 4.41 (td, 1H), 4.23 (s, 2H), 3.70-3.72 (m, 1H), 3.52 (dd, 1H), 3.42 (d, 1H), 3.04-3.08 (m, 1H), 2.94 (s, 3H), 2.90 (dd, 1H), 2.83 (d, 2H), 2.12-2.19 (m, 1H), 1.57-1.59 (m, 2H), 0.67 (d, 6H). LCMS (m/z, Method B) ES+ 531 [M+1]+.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1.P(Br)(Br)[Br:25].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C1C=CC=CC=1>[Br:25][CH2:2][C:3]1[N:4]=[N:5][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(-c2cc(-c3ccccc3)nnc2CBr)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of 3-hydroxymethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.86 g) in tetrahydrofuran (5 ml) was dropwise added to a solution of phosphorus tribromide (0.18 ml) in a mixture of tetrahydrofuran (10 ml) and benzene (5 ml) under ice cooling. After stirring for 4 hours at the same temperature, the reaction mixture was poured into ice-water (50 ml) adjusted to pH 9 with saturated aqueous potassium carbonate and extracted with ethyl acetate (50 ml). The separated organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and acetone (5:1 V/V). The fractions containing the desired compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 3-bromomethyl-4-(3-nitrophenyl)-6-phenylpyridazine (0.73 g).
Reaction SMILES: [Na].[O-]CC.[Na+].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH3:16].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>CCO.O>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[CH2:16][C:17](=[O:23])[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c(F)cccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)C(=O)Cc1c(F)cccc1[N+](=O)[O-]
Yield: 21.3 %

Procedure:
Sodium (2.30 g, 100 mmol) was added to anhydrous EtOH (80 mL) at 0-5° C. for 10 min to prepare a fresh sodium ethoxide solution. A solution of 1-fluoro-2-methyl-3-nitrobenzene (14.4 g, 93.0 mmol) and diethyl oxalate (15.3 g, 105 mmol) in EtOH (80 mL) was added to the above solution, and the resulting mixture was then refluxed for 45 min. After cooling down, the red dark solution was diluted with water (100 mL). After removal of the ethanol, the residue was extracted with EtOAc. The aqueous layer was acidified with 2N HCl to pH around 3 to 4, and extracted with DCM. The organic layers were washed with water, dried, and concentrated to afford 4.5 g (21%) of 3-(2-fluoro-6-nitrophenyl)-2-oxopropanoic acid (32) as red oil. LCMS (ESI) m/z: 245.1 [M+NH4]+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)[CH2:3][CH2:4][C:5](OCC)=[O:6]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCC(N)c1cccc(OC)c1
Solvent: Cc1ccccc1
Product: COc1cccc(C2CCC(=O)N2)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Ethyl 4-amino-4-(3-methoxyphenyl)butanoate (9.39 g) was dissolved in toluene (50 ml) and the solution heated under reflux for 0.5 hr to 1.0 hr. The mixture was cooled to ambient temperature, the precipitate was collected, and the filtrate was concentrated. The residue was recrystallized from ether to give 6.80 g (90%) of product, mp 84°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].O.[SH-:13].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([SH:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nccnc1S
Temperature: 25 °C
Reaction time: 9 h
Yield: 89.4 %

Procedure:
After 3-chloro-pyrazine-2-carboxylic acid methyl ester (0.4 g, 2.3 mmol) was dissolved in MeOH (46 mL), sodium hydrosulfide monohydrate (0.65 g, 6.9 mmol) was added thereto, and the mixture was stirred at room temperature for 9 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl aqueous solution was used to adjust the pH of the reactant to 3. The reactant was extracted with EtOAc, and the organic layer was separated to obtain the title compound (0.35 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][CH2:17][N:18]=[C:7]3[C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2=NCCCN12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1ccc2c(c1)C1=NCCCN1C(=O)N2

Procedure:
Preparation analogously to Example 33 by reduction of 10-nitro-6-oxo-2,3,4,5,6,7-hexahydropyrimido-[1,2-c]-quinazoline using sodium dithionite.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:13]([OH:15])=[O:14])([O-:3])=[O:2].COC(C)(C)C>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[C:5]2[C:13](=[O:14])[O:15][C:7](=[O:9])[C:6]=2[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Product: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.8 %

Procedure:
A solution of 474.8 g (2.25 mol) of 3-nitrophthalic acid in 450 ml of acetic anhydride was stirred under reflux for 1 h. The solution was slowly cooled to 80° C. Then 1000 ml of methyl-tert-butyl ether (MTBE) were added expeditiously and the solution was cooled to 15° C. The resulting solid was isolated, washed with MTBE and dried in a vacuum oven at 40° C. Yield: 88.8%
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4].Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C2CC2)cnc1N
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
A suspension of 3-amino-6-cyclopropylpyrazine-2-carboxylic acid methyl ester (2.17 g, 11.2 mmol), 5-bromopyrimidine (2.5 g, 15.7 mmol), water (425 μl, 23.6 mmol) and potassium carbonate (2.79 g, 20.2 mmol) in o-xylene (43.4 ml) was vented with argon and treated with ultrasound for 2 min. Palladium(II) acetate (101 mg, 0.45 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 325 mg, 0.56 μmol) were consecutively added under inert gas atmosphere and the reaction mixture was heated to 140° C. and stirred for 2 h. After cooling-down to ambient temperature, the reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layers were dried and concentrated in vacuo. The product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as yellow solid (2.49 g, 81.7%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[O:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)=[O:7]>O.O1CCCC1>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.9 %

Procedure:
A solution of lithium hydroxide monohydrate (5.10 g, 121.5 mmol) in water (50 mL) was added to a solution of 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid methyl ester (15.00 g, 48.6 mmol) in tetrahydrofuran (450 mL). The reaction mixture was stirred at room temperature for 72 h. The solvents were evaporated and water was added. The mixture was extracted three times with ether. Insoluble white solid was filtered off. The pH of the aqueous solution was adjusted to 3 and the resulting mixture was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with 50% saturated brine and then evaporated under reduced pressure to give 5-(biphenyl-4-yloxymethyl)-furan-2-carboxylic acid (12.0 g, 84%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]1([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(O)CCC>[C:11]1([O:21][CH2:22][C@H:23]2[CH2:27][CH2:26][CH2:25][N:24]2[C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2c(OCC3CCCN3)cccc2c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1ccc2c(OC[C@H]3CCCN3c3ncnc4[nH]cnc34)cccc2c1

Procedure:
1.6 235 mg of 6-chloropurine, 400 mg of 2(-naphthalen-1-yloxymethyl)pyrrolidine and 0.8 ml of triethylamine are dissolved in 30 ml of 1-butanol and irradiated in the microwave at 120° C. for 6 h. After removal of the solvent in vacuo, the residue is taken up in 10 ml of methanol, the crystals which precipitate in the process are filtered off with suction and washed with methanol, giving 340 mg of colourless crystals 6-[(R)-2-(naphthalen-1-yloxymethyl)pyrrolidin-1-yl]-9H-purine (“A1”); Rt.: 1.806 min; [M+H]+346; m.p. 207-208°;
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:20]=[CH:21][C:22](O)=O>>[CH3:29][O:28][C:26]1[CH:25]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[CH:27]=1)/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)cc(OC)c3)nc2n(CC)c1=O
Yield: 49 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.48 g (16.7 mmol) of 3,5-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/water to give 2.74 g (yield 49%) of Compound 130 as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:24][C:23]([NH:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[N:22][C:21]=3[C:32]([OH:34])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.[N:42]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N.O1CCOCC1>CN(C=O)C>[C:32]([C:21]1[N:22]=[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[O:24][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[CH:19][CH:18]=1)(=[O:34])[NH2:42]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cccnc4)nc3C(=O)O)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(Nc4cccnc4)nc3C(N)=O)cc2)CC1
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(pyridin-3-ylamino)oxazole-4-carboxylic acid (0.046 g, 0.1 mmol) in DMF (1 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.065 g, 0.17 mmol), diisopropylethylamine (0.03 ml, 0.17 mmol) and 0.5M NH3 in dioxane (0.6 ml, 0.3 mmol) and the resultant mixture stirred at room temperature overnight. A further portion of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.020 g, 0.05 mmol), diisopropylethylamine (0.01 ml, 0.056 mmol) and 0.5M NH3 in dioxane (0.2 ml, 0.1 mmol) was added and the reaction stirred for 1 hour. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(pyridin-3-ylamino)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.006 g, 0.013 mmol, 13%). LCMS (2) Rt: 2.64 min; m/z (ES+) 465.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2].[F:17][C:18]1[C:19]([O:25][CH3:26])=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([F:17])[C:19]=3[O:25][CH3:26])[N:11]=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]1=[O:16])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: COc1c(N)cccc1F
Product: CCn1c(=O)ccc2cnc(Nc3cccc(F)c3OC)nc21
Temperature: 175 °C
Yield: 16 %

Procedure:
A mixture of 8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (133 mg, 0.56 mmol) and 500 μL of 3-fluoro-2-methoxyaniline was heated at 175° C. for 20 minutes. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate. Recrystallization from ethyl acetate and hexane provided 28 mg (16%) of 8-ethyl 2-(3-fluoro-2-methoxyphenylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, mp 92-93° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[C:16](=[O:23])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[NH2:17].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:15][C:13]1[CH:14]=[C:2]([NH:17][C:16](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=[C:4]([O:5][C:6]2[CH:7]=[N:8][CH:9]=[N:10][CH:11]=2)[CH:12]=1
Reactant: Clc1cc(Br)cc(Oc2cncnc2)c1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)cc(Oc2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Compound 7 (50 mg, 0.17 mmol, 1.0 eq), tert-butyl carbamate (25 mg, 0.21 mmol, 1.2 eq), sodium tert-butoxide (24 mg, 0.25 mmol, 1.4 eq), Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (5.4 mg, 0.0052 mmol, 0.030 eq), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (8 mg, 0.02 mmol, 0.09 eq) and toluene (0.65 mL) were added to a round-bottom flask, purged with argon and stirred at room temperature overnight. The reaction was filtered over a plug of celite and the plug was washed with 5% MeOH/CH2Cl2. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 41 mg (73%) of the title compound as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.55 (s, 2H), 7.26 (s, 1H), 7.18 (s, 1H), 6.90 (s, 1H), 6.73 (t, J=1.9 Hz, 1H), 1.54 (s, 9H); ES-MS [M+1]+: 322.1.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].I[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu]I.N1CCCC1>[CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC#CI
Reactant: C#CCCCCCC#C
Agent: [Cu]I
Solvent: C1CCNC1
Product: C#CCCCCCC#CC#CCCCCCCCC
Reaction time: 24 h

Procedure:
Pyrollidine (20 mL) and CuI (0.65 g, 3.42 mmol) were added to a nitrogen flushed reaction vessel. Nona-1,8-diyne (1.58 g, 13.17 mmol) was added via syringe. 1-Iodo-1decyne (2.26 g, 8.53 mmol) was added via syringe dropwise to the solution over ten minutes. The reaction was stirred under nitrogen for 24 h. The reaction mix was then quenched with ammonium chloride (10 mL), separated with diethyl ether, and dried with anhydrous magnesium sulfate. Nonadeca-1,8,10-triyne was then isolated using silica column chromatography with a 1% ether/hexane eluting solution obtaining 1.06 g of an oil. 50% yield; 1H NMR (CDCl3) δ 2.29 (m, 4H, CH2—C≡C), 2.22 (dt, 2H, CH2—C≡C, J=7, 2.7 Hz), 1.97 (t, 1H, H—C≡C, J=2.7 Hz), 1.54 (m, 6H, CH2—C—C≡C), 1.33-1.40 (sextuplet, 2H, CH2—CH2—CH3), 1.27 (m, 10H, C—CH2—C), 0.88 (t, 3H, CH3); 13C NMR (CDCl3) δ: 84.62, 77.99, 77.36, 68.63, 65.76, 65.45, 32.21, 29.54, 29.46, 29.25, 28.72, 28.34, 28.31, 28.23, 23.06, 19.61, 19.52, 14.53; MS (ESI) [M+Na]+ calc. 279.2083. Found 279.1723 (very unstable to any MS technique). Elemental analysis calc. for C19H28: C, 88.99; H, 11.01. Found: C, 88.80; H, 10.96.
Reaction SMILES: O.[OH-].[Li+].[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:10][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=2[F:21])[CH2:8]1)#[N:5].Cl>CO.O.C1COCC1>[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:10][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[F:21])[CH2:8]1)#[N:5]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)O)cc2F)C1
Temperature: 35 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Lithium hydroxide monohydrate (83 mg, 2.0 mmol) was added to a mixture of methyl 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoate (0.34 g, 0.79 mmol) in methanol (2.0 mL), water (1.0 mL) and THF (2.0 mL). The reaction mixture was stirred at 35° C. overnight, and adjusted to pH=5 with 1.0 N HCl aqueous solution, and concentrated under reduced pressure to remove methanol and THF. The precipitate formed was filtered, washed with water and ether, and dried in vacuum to afford the desired product (0.17 g, 52%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=417.1.