Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][O:7][CH2:8]Cl.Cl.[Cl:16][C:17]1[CH:18]=[N:19][C:20](=[O:23])[NH:21][CH:22]=1>>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][O:7][CH2:8][N:21]1[CH:22]=[C:17]([Cl:16])[CH:18]=[N:19][C:20]1=[O:23]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: FC(F)(F)c1cccc(COCCl)c1
Agent: Cl
Product: O=c1ncc(Cl)cn1COCc1cccc(C(F)(F)F)c1

Procedure:
was prepared as described in Example 3 from chloromethyl 3-trifluoromethyl-benzyl ether (see Preparation 6a and 6b) (10 mmol) and 5-chloropyrimidin-2-one hydrochloride (10 mmol) in 52%. (1.66 g) yield, m.p. 95° C. 1H NMR (CDCl3): δ4.77 (CH2Ph), 5.42 (CH2O), 7.3-7.7 (Ph), 7.82 and 8.55 (H-4, H-6, J 4 Hz). IR(KBr): 1660 cm-1 (CO).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH2:28][CH2:29][OH:30])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[N:7]([C:17]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:19]([Cl:26])[C:18]=1[CH2:27][CH2:28][CH:29]=[O:30])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO)c(Cl)nc3ccnn23)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCC=O)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a methylene chloride (1.7 mL) solution containing tert-butyl[5-chloro-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-7-yl](4-ethoxyphenyl)carbamate (155 mg, 0.346 mmol), Dess-Martin periodinane (152 mg, 0.381 mmol) was added with ice-cooling, and this mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified with column chromatography (10 to 20% ethyl acetate-hexane) to obtain the title compound (117 mg, yield 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: COc1ccc(I)cc1
Product: COc1ccc(C#CCSc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)cc1

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-iodo-4-methoxy-benzene gave the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NCc2ccc(OCc3ccccc3)cc2)cn1
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 64.4 %

Procedure:
To a solution of 6-aminonicotinic acid (130 mg, 0.941 mmol) and 4-benzyloxy-benzylamine (201 mg, 0.941 mmol) described in Preparation Example 1 in N,N-dimethylformamide (5 mL), was added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (624 mg, 1.41 mmol) and triethylamine (394 μl, 2.82 mmol), and the solution was stirred for 40 minutes at 80° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed twice with water. The solvent was evaporated in vacuo, ethyl acetate was added to the residue, a white insoluble matter was collected by filtration, and 6-amino-N-(4-benzyloxy-benzyl)-nicotinamide (202 mg, 0.606 mmol, 64%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[OH:15].[H-].[Na+].Br[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26]>CN(C)C=O>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([O:15][CH2:24][C:25]([OH:27])=[O:26])[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1nc2ncnn2c(N)c1C#CC(O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2ncnn2c(N)c1C#CC(OCC(=O)O)C1CCCC1
Reaction time: 2 h
Yield: 21 %

Procedure:
To a stirring solution of Example 35B (20 mg, 0.074 mmol) in 0.5 mL of anhydrous N,N-dimethylformamide was added NaH (60%, 4.0 mg, 0.096 mmol). The resulting mixture was stirred for 20 min before tert-butyl bromoacetate (11 μL, 0.0.74 mmol) was added, and stirring continued for 2 h. The reaction mixture was then partitioned between ethyl acetate (10 mL) and brine (10 mL), the organic layer was dried over MgSO4, filtered, evaporated to dryness in vacuuo. The residue was treated with 1.0 mL of 4N HCl in 1,4-dioxane for 3 h. Organic solvent was then removed on a rotavap, and the residue was purified using reverse phase HPLC (C-18 column, eluting with a 5-100% CH3CN gradient in 10 mM ammonium acetate(aq.)) to give the title Compound (5 mg, 21% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.15 (brs, 2H), 4.79-4.60 (m, 2H), 4.34 (d, J=7.1 Hz, 1H), 2.54 (s, 3H), 2.25-2.15 (m, 1H), 1.81-1.38 (m, 8H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[CH:31]=O.N1CCCCC1>C1(C)C=CC=CC=1>[CH3:18][C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[C:9](=[O:16])[C:10](=[CH:31][C:27]1[S:26][CH:30]=[CH:29][CH:28]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=Cc1cccs1
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1cccs1)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (0.50 g), 2-thiophenecarboxaldehyde(0.34 g), piperidine(0.43 g) and molecular sieve 4A in toluene was stirred at 80° C. for 7 hrs. The reaction solution was filtered (celite), evaporated and recrystallised (ethanol) to give ethyl 4-methyl-4-(2,3-dihydro-6-methyl-5-phenyl-4-oxo-4H-1,3-oxazin-3-yl)-2-(2-thienylmethylidene)-3-oxo-pentanoate (Compound 206, 0.20 g), NMR 1.23(t,3H) 1.58(s,6H) 1.94(s,3H) 4.29(q,2H) 5.19(s,2H) 7.05(7.20-7.37(6H) 7.48(1H) 8.05(s,1H). By proceeding in a similar manner the following compounds were also obtained:
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH2:2][CH3:3].[CH2:8]([O:10][C:11](=[O:19])[C:12](=O)[CH:13](Cl)[CH2:14][CH2:15][CH3:16])[CH3:9].N1C=CC=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[N:7]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[S:6][C:13]=1[CH2:14][CH2:15][CH3:16])=[O:19])[CH3:9]
Reactant: CCCC(Cl)C(=O)C(=O)OCC
Reactant: CCCNC(N)=S
Solvent: c1ccncc1
Solvent: CCO
Product: CCCNc1nc(C(=O)OCC)c(CCC)s1
Yield: 68.3 %

Procedure:
n-Propylthiourea (270 mg), 3-chloro-2-oxohexanoic acid ethyl ester (441 mg), and pyridine (0.28 ml) were added to ethanol (10 ml), and the solution was refluxed for 3.5 hours. The solvent was evaporated. The residue was extracted with chloroform (20 ml), and washed with dilute hydrochloric acid solution (10 ml). The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (eluent:chloroform/methanol=100/1), 2-n-propylamino-5-n-propyl thiazole-4-carboxylic acid ethyl ester (400 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=S)=[N:5]1.[NH3:18]>CCO>[OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:18])=[N:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[N:5]1
Reactant: OCCn1ccc(NC(=S)NCC(F)(F)F)n1
Reactant: N
Solvent: CCO
Product: NC(=NCC(F)(F)F)Nc1ccn(CCO)n1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 1-(2-hydroxyethyl)-3-[3-(2,2,2-trifluoroethyl)thioureido]pyrazole (20.0 g.) in 5 N ammonia in EtOH solution (700 ml.) was added yellow mercuric oxide (64.8 g.) with stirring. Stirring was continued for a period of 2 hours. The mixture was filtered through diatomaceous earth and the solvent then evaporated to dryness in vacuo. The residual oil was triturated with ether to give 1-(2-hydroxyethyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (18.5 g.; 99%), m.p. 82°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:19](=[O:20])[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:69]1[CH2:73][CH2:72][C@@H:71]2[CH2:74][N:75]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[CH2:76][C@H:70]12>C1COCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:20]=[C:19]1[N:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:69]4[CH2:73][CH2:72][C@@H:71]5[CH2:74][N:75]([C:77]([O:79][CH2:80][CH3:81])=[O:78])[CH2:76][C@H:70]45)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:15]=[CH:16][CH:17]=[CH:18]1
Reactant: CCOC(=O)N1C[C@H]2CCN[C@H]2C1
Reactant: O=c1cccnn1-c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 70 °C

Procedure:
2-(4′-Bromobiphenyl-4-yl)pyridazin-3(2H)-one (1.92 g, 5.86 mmol), palladium(II) acetate (0.158 g, 0.234 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.407 g, 0.703 mmol) and cesium carbonate (3.06 g, 9.38 mmol) were suspended in 25 mL of THF. A solution of (3aR,6aR)-ethyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate in 10 mL of THF was added and the mixture was heated at 70° C. under N2 for 20 hours. The mixture was allowed to cool to ambient temperature, diluted with 70 mL of EtOAc, and filtered through a ¼ pad of Celite®. The Celite® pad was washed with an additional 70 mL of EtOAc and the filtrate was absorbed on silica gel and chromatographed (eluting with 0-40% EtOAc in DCM) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (dd, J=3.7, 1.7 Hz, 1H), 7.64 (s, 4H), 7.53 (d, J=8.8 Hz, 2H), 7.25 (dd, J=9.8, 3.4 Hz, 1H), 7.07 (dd, J=9.5, 1.7 Hz, 1H), 6.64 (d, J=8.5 Hz, 2H), 4.20-4.32 (m, 1H), 4.12 (q, J=7.5 Hz, 2H), 3.70-3.81(m, 1H), 3.59-3.69 (m, 2H), 3.48-3.58 (m, 1H), 3.36-3.48 (m, 2H), 2.99-3.10 (m, 1H), 2.20 (ddd, J=13.0, 7.3 Hz, 1H), 1.95 (ddd, J=12.9, 6.4 Hz, 1H), 1.24 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 431(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]=1.[ClH:19].C(N(C1(C2C=CC=CC=2)CCN([CH2:31][CH2:32][CH2:33][C:34]2([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=3)[CH2:40][CH2:39][CH2:38][CH2:37][N:36]([C:41](=[O:48])[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:35]2)CC1)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[ClH:55].[ClH:19].[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9][N:10]([CH2:31][CH2:32][CH2:33][C:34]3([C:49]4[CH:54]=[CH:53][C:52]([Cl:55])=[C:51]([Cl:56])[CH:50]=4)[CH2:40][CH2:39][CH2:38][CH2:37][N:36]([C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:35]3)[CH2:11][CH2:12]2)[N:6]=1
Reactant: CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCCN(C(=O)c3ccccc3)C2)CC1
Reactant: Nc1nc(C2(c3ccccc3)CCNCC2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Nc1nc(C2(c3ccccc3)CCN(CCCC3(c4ccc(Cl)c(Cl)c4)CCCCN(C(=O)c4ccccc4)C3)CC2)cs1

Procedure:
This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.77 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.8 g of the expected product after crystallization from AcOEt, m.p.=178° C.
Reaction SMILES: OC[CH2:3][C:4]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[N:28]=4)=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12].I([O-])(=O)(=O)=O.[Na+].O.C(#N)C.[C:49]([O:52]CC)(=[O:51])[CH3:50]>O.[Ru](Cl)(Cl)Cl>[C:49]([CH2:50][CH2:3][C:4]1([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[O:31][N:30]=[C:29]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])[N:28]=4)=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[C:5](=[O:12])[NH:6][C:7](=[O:11])[NH:8][C:9]1=[O:10])([OH:52])=[O:51]
Reactant: O=C1NC(=O)C(CCO)(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)no4)cc3)cc2)C(=O)N1
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: O=C(O)CCC1(Oc2ccc(Oc3ccc(-c4nc(-c5ccccc5F)no4)cc3)cc2)C(=O)NC(=O)NC1=O
Reaction time: 4 h

Procedure:
A mixture of 5-(2-hydroxy-ethyl)-5-{4-[4-(3-(2-fluorophenyl)-[1,2,4]oxadiazol-5-yl)-phenoxy]-phenoxy}-pyrimidine-2,4,6-trione (518 mg, 1.0 mmol), sodium periodate (875 mg, 4.1 mmol), ruthenium trichloride hydrate (7 mg, 0.025 mmol), water (3 mL), acetonitrile (2 mL), and ethyl acetate (2 mL) was stirred vigorously for 4 hours. The mixture was filtered through diatomaceous earth which was then rinsed with ethyl acetate. The filtrate was washed with 10% sodium dithionite solution and brine and then dried over sodium sulfate. Filtration and concentration yielded 418 mg of the title compound as a white solid. LC-MS (m/z, APCI): 533 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([N+:18]([O-])=O)=[C:11]([CH:17]=2)[O:12][CH2:13][CH2:14][C:15]#[N:16])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1.O>[Pd].C(O)C>[Cl:28][C:29]1[N:34]=[C:33]([NH:18][C:10]2[CH:9]=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:17][C:11]=2[O:12][CH2:13][CH2:14][C:15]#[N:16])[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 8 h
Yield: 65.6 %

Procedure:
3-(5-Morpholin-4-yl-2-nitro-phenoxy)-propionitrile (209 mg, 0.754 mmol) and 10% Palladium on Carbon (50% Wet) (120 mg) in Ethanol (45 mL) was shaken under an atmosphere of Hydrogen (45 psi) for 1 h. The mixture was filtered, washing with ethanol, and Triethylamine (0.21 mL, 1.5 mmol) and 2,4,5-Trichloro-pyrimidine (0.13 mL, 1.1 mmol) were added to the filtrate. The mixture was stirred overnight, then poured into 100 mL water, then cooled. The solids were collected by filtration, to give 3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile as a purple solid (195 mg, 66%). 1H-NMR (CDCl3): 8.28 (d, 1H, J=8.0 Hz), 8.16 (s, 1H), 6.65 (d, 1H, J=8.0 Hz), 6.49 (s, 1H), 4.31 (t, 2H, J=5.2 Hz), 3.88 (t, 4H, J=4.1 Hz), 3.15 (t, 4H, J=4.1 Hz), 2.89 (t, 2H, J=5.2 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]([F:28])([F:27])[CH2:17][O:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[N:24][C:19]([O:18][CH2:17][C:16]([F:28])([F:15])[F:27])=[CH:20][CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: NCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)nc1
Yield: 65 %

Procedure:
The title compound is prepared in 65% yield (132 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanamine hydrochloride (138 mg, 0.57 mmol, Amine-11) in a similar manner to Intermediate-2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][N:10]2[C:14](=[O:15])[C:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]2[CH3:25])=[CH:4][CH:3]=1.[N:27]([C:30]1[C:31]([CH3:36])=[N:32][O:33][C:34]=1[CH3:35])=[C:28]=[O:29]>ClCCl>[CH3:36][C:31]1[C:30]([NH:27][C:28]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:26])[CH2:9][N:10]3[C:14](=[O:15])[C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([CH2:16][CH2:17][CH3:18])[N:12]=[C:11]3[CH3:25])=[CH:6][CH:7]=2)=[O:29])=[C:34]([CH3:35])[O:33][N:32]=1
Reactant: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(N)cc2)C1=O
Reactant: Cc1noc(C)c1N=C=O
Solvent: ClCCl
Product: CCCC1(c2ccccc2)N=C(C)N(CC(=O)c2ccc(NC(=O)Nc3c(C)noc3C)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.3 %

Procedure:
A mixture of (+/−)-3-[2-(4-amino-phenyl)-2-oxo-ethyl]-2-methyl-5-phenyl-5-propyl-3,5-dihydro-imidazol-4-one (88 mg, 0.25 mmol) and 4-isocyanato-3,5-dimethyl-isoxazole (35 mg, 0.25 mmol) in 3 mL dichloromethane is stirred at room temperature for 18 hours. Subsequently the solvent is evaporated and the residue is dissolved in acetonitrile, the solution filtrated and subjected to preparative HPLC purification (method 3) to yield (+/−)-1-(3,5-dimethyl-isoxazol-4-yl)-3-{4-[2-(2-methyl-5-oxo-4-phenyl-4-propyl-4,5-dihydro-imidazol-1-yl)-acetyl]-phenyl}-urea (43 mg, 35%), LC/MS at 254 nm; [M+H] 488; Rt 2.648 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[C:9](C)=[CH2:10].OCCON(OCCO)C(=O)C(CC)=C>>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:12])[CH:9]=[CH2:10]
Reactant: C=C(C)C(=O)NCCOCCO
Agent: C=C(CC)C(=O)N(OCCO)OCCO
Product: C=CC(=O)NCCOCCO

Procedure:
According to the same process, N-(2-hydroxyethoxy)ethyl-methacrylamide and N,N-di(2-hydroxyethoxy)ethyl-acrylamide are obtained.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[CH3:29]>>[NH2:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]([C:10]2[CH:9]=[C:8]([N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH3:17])[N:13]=[CH:12][N:11]=2)=[O:16])=[C:20]([CH3:29])[CH:21]=1)(=[O:26])=[O:27]
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)c1cc(N(C)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-3-methyl-benzenesulfonamide (Biofine), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [NH2:1]CCC[Si](OC)(OC)OC.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[CH:17]([OH:20])(C)[CH3:18]>C(OCCCC)(=O)C>[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[NH2:1][C:12]([O:20][CH2:17][CH3:18])=[O:16]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: CC(C)O
Agent: C=CC(=O)O
Solvent: CCCCOC(C)=O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 9.94 g of 3-aminopropyltrimethoxysilane and 15.4 g of hexanedioldiacrylate is stirred at room temperature for 3 hours. To the mixture, 28.5 g of PM glycol ether is added. The resulting mixture is stirred at room temperature for 1 minute. Then, 1.73 g of acrylic acid is added, and the mixture is stirred for 5 minutes. The mixture is diluted by adding 106.7 g of isopropanol. Next, 84.4 g of OG401-31 and 34.7 g of NALCO 1034A are added under vigorous agitation. The resulting mixture is stirred at room temperature for 1 hour. 0.74 g of a solution of EBECRYL 1360 (50% by weight in PM glycol ether), 3.98 g of DAROCUR 1173, and 64.8 g of n-butyl acetate are added. The resulting coating composition is stirred for an additional 30 minutes to ensure mixing.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([C:13]3([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>CCOC(C)=O>[CH3:18][C:13]1([C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:23]4[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=4)[N:3]=3)[NH:8][CH:9]=2)=[O:12])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCC1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CCCC4)c3n2)cc(OC)c1OC

Procedure:
(1-Methyl-cyclopentyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone was prepared starting from (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclopentyl)-methanone and 3,4,5-trimethoxyphenylboronic acid following general procedures as described in these Examples. Silica gel chromatography using 2-50% EtOAc in hexanes as eluant gave a pale brown solid which was washed with 1:1 Et2O/Hexanes provided 10 mg (7.7%) of an off white solid. MP 244-246° C., M+H=396.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[CH3:27][O:28][CH2:29][C@H:30]([O:32][C:33]1[CH:42]=[C:41]2[C:36]([CH:37]=[CH:38][C:39]([CH:43]=O)=[N:40]2)=[CH:35][CH:34]=1)[CH3:31].C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:43]([C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[CH:42][C:33]([O:32][C@H:30]([CH3:31])[CH2:29][O:28][CH3:27])=[CH:34][CH:35]=4)[N:40]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COC[C@@H](C)Oc1ccc2ccc(C=O)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC[C@@H](C)Oc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.6 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.17 g, 0.44 mmol) and (R)-7-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.11 g, 0.44 mmol) in ethanol (2.2 mL, 0.44 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.16 g, 0.49 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.11 g, 42%).