Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:17])([CH3:16])[C:9]([O:11]C(C)(C)C)=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[C:3]([C:8]([CH3:17])([CH3:16])[C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)c1nccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1nccnc1Cl
Yield: 59.2 %

Procedure:
The tert-butyl ester from step 1 was dissolved in a mixture of dichloromethane (40 mL) and trifluoroacetic acid (20 mL) and heated at reflux. After 4 hours the solution was evaporated to dryness under reduced pressure and purified using silica chromatography (0-10% methanol in dichloromethane gradient) to give 2-(3-chloropyrazin-2-yl)-2-methylpropanoic acid (5.70 g, 28.4 mmol, 59.2% yield) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11](S)=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:17])=O.CN(C=O)C>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([Cl:17])=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2nc(S)oc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(Cl)oc12
Yield: 80.1 %

Procedure:
To 2-mercapto-benzooxazole-7-carboxylic acid methyl ester (1.0 g, 4.78 mmol, 1.0 equiv) was added thionyl chloride (8.0 g, 4.9 mL, 67.6 mmol, 14.0 equiv) and anhydrous DMF (0.4 g, 0.4 mL, 5.19 mmol, 1.1 equiv) and the reaction mixture heated to reflux for 15 min. The solvent was removed under reduced pressure, the crude oil azeotroped twice with xylene and the crude material purified with column chromatography on silica eluting with ethyl acetate/hexane (1:1) to afford 0.81 g (81%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.03 (s, 3H), 7.44 (t, J=7.9 Hz, 1H), 7.87 (dd, J=7.9 Hz, J=1.1 Hz, 1H), 8.01 (dd, J=7.9 Hz, J=1.1 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 52.46, 115.07, 124.36, 124.82, 127.54, 142.39, 150.35, 152.24, 163.88. MS (ISP): 212.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[NH:16][N:15]=[C:14]([NH:17][C:18]3[CH:27]=[CH:26][N:25]=[C:24]4[C:19]=3[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22](=[O:28])[NH:23]4)[CH:13]=2)[CH:5]=[CH:6][C:7]=1F.FC1C=C(C=CC=1)N>>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[NH:16][N:15]=[C:14]([NH:17][C:18]3[CH:27]=[CH:26][N:25]=[C:24]4[C:19]=3[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=3[C:22](=[O:28])[NH:23]4)[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n[nH]1)Nc1ccc(F)c(F)c1
Agent: Nc1cccc(F)c1
Product: O=C(Cc1cc(Nc2ccnc3[nH]c(=O)c4ccccc4c23)n[nH]1)Nc1cccc(F)c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 300 using the carboxylic acid intermediate from example 313 and 3-fluoroaniline to provide 314. LC-MS (M+H=429, obsd.=429).
Reaction SMILES: [N+]([C:4]([CH:7]1[CH:11]([O:12]C)[O:10][C:9](=[O:14])[CH2:8]1)([CH3:6])[CH3:5])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH:11]([C:7](=[C:4]([CH3:6])[CH3:5])[CH2:8][C:9]([OH:14])=[O:10])=[O:12]
Reactant: COC1OC(=O)CC1C(C)(C)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)=C(C=O)CC(=O)O
Temperature: 0 °C
Reaction time: 120 h
Yield: 74.6 %

Procedure:
A solution of 18.2 g of the product of Step A in 25 ml of methanol were added all at once to a solution of 18.9 g of sodium carbonate in 180 ml of water cooled to 0° C. and the mixture stood at room temperature for 120 hours. The mixture was washed with ether and cooled to 0° C. after which concentrated sulfuric acid was added to the mixture under an inert atmosphere until the pH was ≅1. The mixture was extracted with chloroform and then with ethyl acetate and the combined organic phases were dried and evaporated to dryness under reduced pressure to obtain 9.5 g of residue. The latter was crystallized from water to obtain 7.4 g of pure 3-formyl-4-methyl-pent-3-one-1-oic acid melting at 102° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl[C:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([CH3:20])[C:12](=[O:21])[CH2:11][N:10]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:20][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:9]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:10][CH2:11][C:12]1=[O:21]
Reactant: C1CCNCC1
Reactant: CN1C(=O)CN=C(Cl)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)CN=C(N2CCCCC2)c2ccccc21
Temperature: 25 °C
Yield: 48.2 %

Procedure:
Piperidine (1.34 g) was added to a solution of crude 5-chloro-1,2-dihydro-1-methyl-3H-1,4-benzodiazepin-2-one hydrochloride (0.005 mol) in dichloromethane (50 ml) cooled in ice. After warming to room temperature, sodium bicarbonate solution (20 ml) was added. The organic phase was separated, dried (Na2SO4) and evaporated to give an orange oil which was purified by column chromatography on silica with CH2Cl2 →CH2Cl2 :MeOH 95:5 as eluant to afford 0.62 g of product as an orange gum 1H NMR (250 MHz, CDCl3) δ: 1.5-1.8 (6H, m), 3.15-3.4 (4H, m), 3.4 (3H, s), 3.5 and 4.25 (2H, ABq, J=11Hz), 7.15-7.6 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]2[C:7]3[N:8]=[C:9]([NH:11][C:12]#[N:13])[S:10][C:6]=3[CH2:5][C:4]=2[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]2[C:7]3[N:8]=[C:9]([NH:11][C:12]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[NH:13])[S:10][C:6]=3[CH2:5][C:4]=2[CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CNc1nc2c(s1)Cc1cc(Cl)ccc1-2
Solvent: CCO
Product: N=C(Nc1ccccc1)Nc1nc2c(s1)Cc1cc(Cl)ccc1-2

Procedure:
0.26 g of 6-chloro-8H-indeno[1,2-d]thiazol-2-yl-cyanamide is suspended in 10 ml of ethanol at room temperature and, after addition of 0.1 of aniline, heated to reflux for 6 h. The reaction mixture is concentrated in vacuo, and the residue is purified by chromatography on silica gel with 5/1 dichloromethane/ethyl acetate. N-(6-Chloro-8H-indeno[1,2-d]thiazol-2-yl)-N′-phenylguanidine is obtained and melts with decomposition at 210° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12]
Reactant: OCc1n[nH]c2ccc(F)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1n[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
A solution of (5-fluoro-1H-indazol-3-yl)methanol (0.215 g, 1.29 mmol) in ethyl acetate (10 mL) was added with manganese dioxide (1.12 g, 12.9 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, then the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 5-fluoro-1H-indazole-3-carbaldehyde (0.150 g, 70%).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:11])=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].C[N:15](C=O)C>>[F:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:11])=[CH:9][N:10]([NH2:15])[C:5]2=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2ccc(F)nc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2ccc(F)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-fluoro-3-methyl-1H-pyrrolo[3,2-b]pyridine (10.7 mmol) in anhydrous DMF (15 mL) is added drop-wise to a stirred solution of NaH (60%, 160 mmol) in anhydrous DMF (25 mL) under N2 at 0° C. for 20 min and stirred at 0° C. under N2 for 30 minutes. HOSA (53.5 mmol) is added portion-wise for 30 minutes at 0° C., and stirred at 0° C. for 1.5 hours. After quenching with ice-water (400 mL), the mixture is extracted with ether (3×60 mL). The combined organic layer is washed with water (2×30 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-60% EtOAc in heptane to afford 5-fluoro-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (570 mg). MS: 166 (M+H); 1H NMR (300 MHz, CDCl3) δ 2.32 (s, 3H), 4.82 (br, 2N—H), 6.76 (d, H), 7.17 (s, H), 7.77 (dd, H).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:25]#[C:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][N:5]=[C:4]([N:9]=[CH:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:3]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)N(C=Nc1ncc(I)c(Cl)n1)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CC(C)N(C=Nc1ncc(C#Cc2ccccc2)c(Cl)n1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2.46 g 4-chloro-2-diisopropylaminomethyleneamino-5-iodopyrimidine, 7.5 mL triethylamine, 0.064 g copper iodide, 0.12 g dichlorobis(triphenyl)phosphine palladium II and 0.9 mL phenylacetylene was stirred under nitrogen at room temperature for two days. The dark brown mixture was evaporated in vacuo at a bath temperature of 30–35° C. The residue was partitioned between dichloromethane and water. The organic phase was washed thrice with water, dried over sodium sulfate, filtered and evaporated to yield 3.37 g of a dark brown oil. The residue was dissolved in hexanes and purified by column chromatography on silica gel, eluting successively with hexanes, 1:1 dichloromethane/hexanes and dichloromethane. The product was obtained from the latter eluant to yield after evaporation, 1.69 (74%) g of 4-chloro-2-diisopropylaminomethyleneamino-5-phenylethynylpyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[C:31]([O:35][C:36]([NH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([O:35][C:36]([NH:38][CH:39]1[CH2:40][CH2:41][N:42]([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:43][CH2:44]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 150 °C
Yield: 65.3 %

Procedure:
A mixture of 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) (150 mg, 0.35 mmol) and 4-(N-tert-butoxycarbonylamino)piperidine (700 mg, 3.5 mmol) were added to dioxane (4 ml) and heated in a sealed vessel under microwave irradiation at 150° C. for 60 minutes. The crude reaction mixture was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). The product containing fractions were passed down an SCX-2 column eluting with methanol and then releasing the product with 2N methanolic ammonia. The solvent was removed by evaporation to give the title compound (134 mg, 64%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[C:5]=2[CH2:16][O:17][CH:18]2[CH2:24][CH:23]3[N:25](C(OC(C)(C)C)=O)[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O.ClCCl>[CH:23]12[NH:25][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]([O:17][CH2:16][C:5]1[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])=[N:7][O:8][C:4]=1[CH:1]1[CH2:2][CH2:3]1)[CH2:24]2
Reactant: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The previous amine, tert-Butyl 3-((5-cyclopropyl-3-(o-tolyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.60 g, 3.65 mmol) was dissolved in trifluoroacetic acid in dichloromethane (30 mL, 20% solution) at RT. The solution was stirred for 1 hour at RT and the solvent was evaporated. The residue was dissolved in ethyl acetate (125 mL), washed with a saturated solution of sodium bicarbonate (100 mL), the organic layer was dried with magnesium sulfate and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-20% ethanol/dichloromethane to afford the desired product as a colorless oil. 1H-NMR (DMSO-d6, 400 MHz) δ 8.44 (bs, 1H), 7.43-7.34 (m, 2H), 7.32-7.28 (m, 2H), 4.21 (s, 2H), 3.83 (bs, 2H), 3.55 (t, J=4.0 Hz, 1H), 2.35-2.28 (m, 1H), 2.20 (s, 3Hc-1.70 (m, 8H), 1.16-1.06 (m, 4H). MS m/z 339.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]([NH:23][C:24]4[C:29]([N+:30]([O-])=O)=[CH:28][CH:27]=[CH:26][N:25]=4)[CH:20]=[CH:21][CH:22]=3)[CH:12]=[N:13][CH:14]=2)=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>C(O)C.O.[Fe]>[NH2:30][C:29]1[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17](/[CH:16]=[CH:15]/[C:11]3[CH:12]=[N:13][CH:14]=[C:9](/[CH:8]=[CH:7]/[C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)[CH:10]=3)[CH:18]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccnc1Nc1cccc(/C=C/c2cncc(/C=C/c3ccncc3)c2)c1
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
A mixture of 2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]-3-nitropyridine (331 mg), iron powder (132 mg) and ammonium formate (297 mg) in ethanol (6 ml) and water (2 ml) was stirred at 90pbC. for 30 minutes. The mixture was filtered while hot. The filtrate was added to aqueous sodium bicarbonate solution and extracted with ethyl acetate twice. The combined organic solution was washed with sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was washed with diisopropyl ether to give 3-amino-2-[3-[(E)-2-[5-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]vinyl]phenylamino]pyridine (270 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([F:20])([F:19])[F:18])[C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=3)=[N:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br.C1CCCCC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([F:20])([F:18])[F:19])[C:10]([C:21]3[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nn(-c3ccc(Br)cc3)c3c(C(F)(F)F)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(-c3ccc(Br)cc3)c3c(C(F)(F)F)cccc23)cc1
Yield: 11.5 %

Procedure:
Prepared according to Method C step B from 1-(4-bromophenyl)-3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.5 mmol), boron tribromide (0.188 mL, 2.0 mmol) and 0.2 mL of cyclohexene to give the product (0.025 g) as a tan solid.
Reaction SMILES: Br[C:2]1[C:3]([CH3:17])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:4]1[C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=[C:2]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:3]=1[CH3:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(N)cc1
Reactant: Cc1c(Br)cc2c(c1C(C)(C)C)OCC2(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Yield: 99.1 %

Procedure:
Following general procedure K and using 5-bromo-7-t-butyl-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 51, 0.33 g, 1.1 mmol), p-anisidine (0.25 g, 2 mmol), sodium tert-butoxide (0.2 g, 2.1 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.030 g, 0.03 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.060 g, 0.096 mmol) in 3 mL of anhydrous toluene, the title compound (0.37 g, quantitative yield) was obtained as a pink solid. 1H NMR (300 MHz, C6D6): δ 6.79 (d, 2H, J=8.9 Hz), 6.72 (s, 1H), 6.60 (d, 2H, J=8.7 Hz), 4.60 (br s, 1H), 3.90 (s, 2H), 3.35 (s, 3H), 2.37 (s, 3H), 1.68(s, 9H), 1.02 (s, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:40][CH2:41][C:42]1[NH:43][C:44](=[O:52])[C:45]2[CH:51]=[CH:50][CH:49]=[N:48][C:46]=2[N:47]=1>CN(C=O)C>[O:52]=[C:44]1[NH:43][C:42]([CH2:41][NH:40][C:9](=[O:11])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:47][C:46]2[N:48]=[CH:49][CH:50]=[CH:51][C:45]1=2
Reactant: NCc1nc2ncccc2c(=O)[nH]1
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CCc1ccccc1)NCc1nc2ncccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 3-phenylpropionic acid [501-52-0] (66.6 mg, 0.444 mmol) in DMF (4 ml) was added EDCI [25952-53-8] (102 mg, 0.532 mmol), HOBt [2592-95-2] (8 mg, 0.059 mmol) and NMM [109-02-4] (0.15 ml, 1.18 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h, and then was added to a solution of the salt of 2-aminomethyl-3H-pyrido[2,3-d]pyrimidin-4-one (CH3CO2H, HBr) (100 mg) in DMF (2 ml). Stirring was continued for 18 h, the solvents were evaporated and the residue as redissolved in EtOAc/THF and a saturated solution of ammonium chloride. The inorganic layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtrated and evaporated. Column chromatography with CH2Cl2/MeOH 9:1, followed by trituration with TBME gave N-(4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide (43.1 mg, 47%) as a off-white solid, MS (m/e): 309 [M+H+].
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=O)[C:12]([F:15])([F:14])[F:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:17][NH:18][NH2:19].C(OCC)(=O)C.CCCCCCC>C(O)C.ClCCl>[CH3:17][N:18]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:19]1
Reactant: CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (10 g, 0.042 mole) was dissolved in ethanol (120 ml) and cooled to 0° C. Methyl hydrazine (2.11 g, 0.046 mole) (pre-stirred in concentrated HCl (4 ml)-EtOH (4 ml), 0° C., 30 min) in EtOH (20 ml) was added at 0° C., and the resulting solution was stirred at room temperature for 18 h. The yellow solution was evaporated and the residue suspended in water and basified with sodium carbonate solution (saturated) and extracted with ethyl acetate (3×30 ml). The organic layer was separated and back-washed with brine (2×30 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give an oil. Yield 7 g. 1H NMR (300 MHz, CDCl3) shows 6:1 for desired regioisomer. The oil was dissolved in dichloromethane and purified using an ISCO Companion (70 g silica col., heptane to ethyl acetate:heptane 1:1). The appropriate fractions were combined and evaporated to give a colourless oil, 5.71 g, Yield 62%. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H) 4.36, 4.34, 4.32, 4.30 (q, 2H) 4.08 (s, 3H) 1.38, 1.36, 1.34 (t, 3H). MS (ESI): m/z 223 (M+H)+. LC-MS ELSD 100% m/z 223 (M+H)+. TLC Ethyl acetate:heptane 1:1 0.7 UV+ve
Reaction SMILES: Br.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]2.[C:20](=O)([O-])[O-].[K+].[K+].C(Br)CBr.Cl>CN(C)C=O.C(#N)C.O>[CH2:20]1[O:2][C:3]2[CH:4]=[C:5]3[C:9]([CH2:8][CH:7]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:6]3)=[CH:10][C:11]=2[O:12]1
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCC)C1Cc2cc(O)c(O)cc2C1
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: BrCCBr
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)OCO3
Temperature: 100 °C

Procedure:
5,6-Dihydroxy-2-(di-n-propylamino)indan hydrobromide (400 mg, 1.21 mmol) was dissolved in dimethylformamide/acetonitrile (8 mL, 1:1). Potassium carbonate (1.67 g, 12.1 mmol) and 1,2-dibromomethane (0.09 mL, 1.3 mmol) was added and the mixture was heated at 100° C. overnight. Water was added and the reaction mixture concentrated to remove solvents. The resulting mixture was extracted with ethyl acetate (5×75 mL). The combined organic layers were washed with brine, dried, filtered and concentrated to yield an oil. The crude material was chromatographed (200 g silica gel) eluting with methylene chloride/methanol (19:1) to yield an oil. The oil was converted into the HCl salt and recrystallized using methanol/ethyl acetate/ether: mp 168°-269° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Cl[CH2:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.OCC1N=CC=CN=1.S(Cl)(Cl)=O>>[N:8]1[CH:9]=[CH:10][CH:11]=[N:12][C:7]=1[CH2:6][NH:3][CH2:2][CH2:1][NH2:4]
Reactant: ClCc1ncccn1
Reactant: NCCN
Agent: OCc1ncccn1
Solvent: O=S(Cl)Cl
Product: NCCNCc1ncccn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 2-chloromethylpyrimidine, prepared by treating 2-hydroxymethylpyrimidine with thionyl chloride, to give N-(2-pyrimidylmethyl)ethylenediamine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([C:8](=[O:17])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: Cc1ccccc1CC(=O)c1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1cccc(I)c1)c1ccccc1C

Procedure:
A solution of 1-(3-iodophenyl)-2-(2-methylphenyl)ethanone (3.21 g) in dry tetrahydrofuran (30 mL) is treated with methyl acrylate (0.9 mL) and potassium tertiary butoxide (0.107 g). The reaction mixture is heated at reflux for 18 hours, evaporated and the residue partitioned between ethyl acetate (60 mL) and water (30 mL). The organic phase is dried over magnesium sulphate, evaporated and the residual solid washed with pentane to give methyl (RS)-5-(3-iodophenyl)-4-(2-methylphenyl)-5-oxopentanoate as a fawn coloured solid (3.39 g), m.p. 106-108° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][C:13]([C:11]1[CH:12]=[C:7]([C:5]2[S:6][C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[N:3][N:4]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[OH:17])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-c2nnc(NS(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
A slurry of 0.52 g (1.7 mmol) of 4-(5-amino-1,3,4-thiadiazol-2-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.26 g (2.58 mmol) of triethylamine in 6 ml of toluene is treated with 0.30 g (2.58 mmol) of methane sulfonylchloride and warmed at 95°-105° C. for 21 hours under Nitrogen atmosphere. The reaction is cooled to room temperature and poured onto cold aqueous 1N NaOH (100 ml) and extracted with t-butylmethyl ether (3×20 ml). The aqueous layer is acidified with aqueous 1N HCl and filtered to give a yellow solid. Recrystallization from absolute ethanol gives 0.19 g (0.65 g, theor., 29%) of N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]methanesulfonamide as a solid: mp 293°-294° C.