Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C)CC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 120 mg (0.33 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 55 μL (0.50 mmoL) N-methyl piperazine, 139 mg (0.37 mmol) HATU and 96 μL DIPEA in 1.2 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/MeOH-gradient. Yield: 55 mg (37%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)([O:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)[CH3:5]>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[C:4]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)(Oc1ccccc1)c1ccc(O)cc1
Yield: 90 %

Procedure:
A solution of 4-Benzyloxyphenyl-2-(4-chlorophenoxy)propanoic acid methyl ester in ethanol with 10% Pd/C (5 wt %) was stirred under hydrogen atmosphere (1 tm) over 2 hours. The catalyst was removed via filtration through a pad of celite and the filtrated concentrated in vacuo to produce the title compound (90%). 1H-NMR (200.15 MHz, CDCl3): δ 7.25–7.14 (m, 4H), 7.94–7.73 (m, 4H), 4.81–4.69 (m, 1H), 3.70 (s, 3H), 3.16 (d, 2H, J=4.1).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[F:5][CH:6]([C:11](OC)=[O:12])[C:7](OC)=[O:8].C[O-].[Na+]>CO>[F:5][C:6]1[C:7](=[O:8])[NH:1][C:2](=[O:3])[NH:4][C:11]=1[OH:12]
Reactant: NC(N)=O
Reactant: COC(=O)C(F)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]c(O)c(F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A mechanically stirred solution of urea (60.06 g, 1 mol) and dimethyl fluoromalonate (150.11 g, 1 mol) in methanol (1 L) was treated with 25 wt % NaOMe in methanol (˜4.6 M, 435 mL, 2 mol). The mixture was refluxed for 3 h and then allowed to cool to room temperature. The mixture was filtered, the wet cake was dissolved in warm water (˜1.2 L), and the resulting aqueous solution was acidified with concentrated aqueous HCl (˜160 mL) to pH=2 while stirring over 1 h. The mixture was allowed to cool to room temperature, and the product was filtered and washed thoroughly with water, then dried under vacuum to give 5-fluoro-6-hydroxy-2,4(1H,3H)-pyrimidinedione (80 g, 55%) as a white solid. LCMS: (M+H)+: 147.0.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)\[C:11]2[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=2)[N:6]=1.N1C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](\[C:11]3[N:12]([CH3:17])[O:13][C:14](=[O:16])[N:15]=3)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:6]=2)=[O:39])=[CH:33][CH:32]=1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(NC(=O)Cc2ccc(Cl)cc2)n1)c1ccccc1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (300 mg, 0.905 mmol, 1 eq.) and pyridine (0.110 ml, 1.36 mmol, 1.5 eq) in dry dichloromethane (4.0 ml) at room temperature was added 4-chlorophenyl acetyl chloride (0.20 mL, 1.36 mmol, 1.5 eq) and stirring was allowed for 2 h. The reaction was quenched by addition of 2 ml of 1N NaOH. The layers were separated and the organic layer was dried over MgSO4. After concentration, the residue was purified by chromatography on silica gel to give 2-(4-chlorophenyl)-N-{4-[({[(Z)-(2-methyl-5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)(phenyl)methylene]amino}oxy)methyl]-1,3-thiazol-2-yl}acetamide (365 mg, 79% yield).
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[N:10]=[C:9]([F:11])[C:8]([F:12])=[C:7](F)[C:6]=1[F:14].[CH3:15][NH:16][CH3:17]>O>[CH3:15][N:16]([CH3:17])[C:7]1[C:6]([F:14])=[C:5]([F:4])[N:10]=[C:9]([F:11])[C:8]=1[F:12]
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)c1c(F)c(F)nc(F)c1F
Reaction time: 0.5 h

Procedure:
To methylene chloride (50 mL) cooled in an ice bath was added pentafluoropyridine (2.0 g, 11.8 mmol) and dimethylamine (2.97 mL of a 40% solution in water, 24 mmol). After stirring for 30 minutes the solution was washed with water, and dried over basic alumina. The solvent was removed in vacuo to give 4-dimethylamino-2,3,5,6-tetrafluoropyridine; NMR (CDCl3) 3.13 (m,6) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[N:8]([CH2:17][C:18]([OH:20])=O)[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]1=2.[NH2:26][CH2:27][C:28]1[N:29]=[C:30]([NH:33][C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[S:31][CH:32]=1>>[CH2:37]([NH:36][C:34]([NH:33][C:30]1[S:31][CH:32]=[C:28]([CH2:27][NH:26][C:18](=[O:20])[CH2:17][N:8]2[C:9](=[O:16])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:25])[C:6]3[CH:24]=[CH:23][CH:22]=[CH:21][C:7]2=3)[N:29]=1)=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NCc1csc(NC(=O)NCc2ccccc2)n1
Reactant: COC(=O)CN1c2ccccc2C(=O)N(CC(=O)O)c2ccccc21
Product: COC(=O)CN1c2ccccc2C(=O)N(CC(=O)NCc2csc(NC(=O)NCc3ccccc3)n2)c2ccccc21

Procedure:
Preparation took place in analogy to I.B.23 by reacting [5-(2-methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo[b,e]-[1,4]diazepin-10-yl]acetic acid 37c with N-[4-(aminomethyl)1,3-thiazol-2-yl]-N′-benzylurea (hydrochloride) (38). Chromatography on silica gel (CH2Cl2/CH3OH 2→10%) afforded 0.45 g; ESI-MS [M+H+]=585.25.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].Cl.[CH3:27][CH:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=1)[CH3:29]>CN(C=O)C>[C:24]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[N:43]1[CH2:42][CH2:41][N:40]([C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:28]([CH3:29])[CH3:27])=[CH:32][CH:33]=3)=[O:39])[CH2:45][CH2:44]1)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH:7]=2)#[N:25]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCC1CCCNC1
Reactant: CC(C)Oc1ccc(NC(=O)N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(N3CCN(C(=O)Nc4ccc(OC(C)C)cc4)CC3)c(C#N)cnc2cc1OCCCC1CCCNC1
Temperature: 40 °C

Procedure:
To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487 mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed by N-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g, 0.535 mmol). The reaction mixture was heated to 40° C. overnight, during that period starting materials were consumed. After cooling diluted with EtOAc/water and the layers were separated. The organic layer was dried, filtered and evaporated to afford desired product as a crude residue. The crude residue was purified by RP-HPLC to afford {4-[3-cyano-6-methoxy-7-(3-piperidylpropoxy)quinolin-4-yl)piperazinyl}-N-[4-(methylethoxy)phenyl]carboxamide as the desired product (0.195 g, 69%). MS(ES) 587.3 (M+H)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:12][CH3:13].[Cl:14]C1C=CC(N)=CC=1OC>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(N)ccc1Cl
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: COc1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-chloro-3-methoxy-phenylamine.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C(NCCO)c1ccccc1
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a solution of ethanolamine (1.09 g, 17.8 mmol) in THF was added benzoyl chloride (520 mg, 3.60 mmol) dropwise at 0° C. under N2 atmosphere. The reaction mixture was stirred for 10 min and then quenched with 1M HCl. The mixture was then diluted with EtOAc and washed with sat. aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallized to give N-(2-hydroxyethyl)benzamide (593 mg, 97%) as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ3.41 (s, 1H), 3.49-3.59 (m, 2H), 3.75 (t, 2H, J=5.2 Hz), 7.10 (s, 1H), 7.32-7.38 (m, 2H), 7.42-7.48 (m, 1H), 7.72-7.76 (m, 2H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:25])=[C:5]2[C:20]([C:21]([NH:23][NH2:24])=[O:22])=[N:19][NH:18][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])#[N:2].[CH2:26]([N:28]([CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][N:32]=[C:33]=S)[CH3:27].Cl.C(N=C=NCCCN(C)C)C.O>CC(N(C)C)=O>[CH2:26]([N:28]([CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][NH:32][C:33]1[O:22][C:21]([C:20]2[C:5]3[C:6](=[N:7][C:8]([C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=4[F:17])=[C:3]([C:1]#[N:2])[C:4]=3[CH3:25])[NH:18][N:19]=2)=[N:23][N:24]=1)[CH3:27]
Reactant: COc1ccc(-c2nc3[nH]nc(C(=O)NN)c3c(C)c2C#N)c(F)c1
Reactant: CCN(CC)CCCN=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CC)CCCNc1nnc(-c2n[nH]c3nc(-c4ccc(OC)cc4F)c(C#N)c(C)c23)o1
Temperature: 65 °C
Yield: 60.6 %

Procedure:
To 200 mg (0.59 mmol) of 5-cyano-6-(2-fluoro-4-methoxyphenyl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-3-carbohydrazide diluted in 8 ml of dimethylacetamide, are added 101 mg of N,N-diethyl-3-isothiocyanatopropane-1-amine. The reaction mixture is stirred at 65° C. until complete disappearance of the starting product. 224 mg (1.17 mmol) of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride are added and the solution is stirred at 70° C. for 2 h. 20 ml of water are added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The solid is triturated in a diethyl ether/methanol mixture (10:1) to yield 170 mg of 3-(5-(3-(diethylamino)propylamino)-1,3,4-oxadiazol-2-yl)-6-(2-fluoro-4-methoxyphenyl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a pink solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].[Li+].[OH-].Cl>O1CCCC1.O.CCOCC>[NH2:1][C@@H:2]1[CH2:7][C:6]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)=[CH:5][CH2:4][C@H:3]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: CCOC(=O)[C@H]1CCCN(CC2=CC[C@@H](c3ccc(Cl)cc3Cl)[C@H](N)C2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H]1CC(CN2CCC[C@H](C(=O)O)C2)=CC[C@H]1c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of Example 17B (55 mg, 0.13 mmol) in a mixture of tetrahydrofuran/H2O (1.0 mL/0.5 mL), LiOH (19 mg, 0.80 mmol) was added at room temperature. The reaction mixture was stirred overnight. It was acidified with 2N HCl in ether until pH=3 and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (32 mg, 63%). 1H NMR (400 MHz, methanol-d4) δ ppm 7.78 (s, 1H), 7.55-7.52 (m, 1H), 7.42-7.38 (m, 1H), 6.21 (s, 1H), 4.0-3.90 (m, 1H) 3.85-3.70 (m, 2H), 3.65-3.50 (m, 1H), 3.20-2.8 (m, 3H), 2.75-2.55 (m, 3H), 2.50-2.40 (m, 3H), 2.35-2.20 (m, 2H), 2.05-1.85 (m, 2H). MS (APCI) m/z 383 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([NH:15]C(OCC2C=CC(OC)=CC=2)=O)[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH:14]([NH2:15])[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:28]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(COC(=O)NC2CC=CCN(S(=O)(=O)c3ccc(OC)cc3)C2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC=CCC(N)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-(4-methoxybenzyloxy carbonyl-amino)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester (370 mg, 0.71 mMol) is dissolved in Dichloromethane (15 ml) containing 3% Trifluoroacetic Acid. The reaction is stirred for 1 h at room temperature. The solvents are evaporated and the remaining oil is co-evaporated twice with Toluene. Flash-chromatography Dichloromethane/Methanol (7:1) to afford the free amine: Cal. 546.6 found (M)+=547.
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[CH:9][N:10]=1)([CH3:5])[CH2:3][OH:4].[P:30](Cl)([O:35]CC)([O:32]CC)=[O:31].C(N(CC)CC)C.Br[Si](C)(C)C>C(Cl)Cl>[P:30]([OH:35])([OH:32])([O:4][CH2:3][C@:2]([NH2:1])([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:28])([F:29])[F:27])[CH:12]=2)=[CH:9][N:10]=1)[CH3:5])=[O:31]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCCCCCCCOc1ccc(-c2cnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(-c2cnc([C@@](C)(N)COP(=O)(O)O)s2)cc1C(F)(F)F

Procedure:
E1 (25 mg, 1.0 equiv), DCM (5 mL), diethyl chlorophosphate (85 μL, 10.0 equiv) and triethylamine (165 μL, 20.0 equiv) were stirred overnight. The obtained phospho-diester intermediate was reacted with excess bromotrimethylsilane in DCM for 5 hrs. The resulting phosphate was purified by preparative HPLC as the trifluoroacetate salt (10 mg). MS (ESI, M+H+)=511.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N[C:21](N)=[O:22].O>CN1C(=O)CCC1>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:21](=[O:22])[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cc(Oc2ccc(F)cc2F)ccc1N
Reactant: NC(N)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Oc3ccc(F)cc3F)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Compound (1D) (23 g, 0.09 mol) and urea (25.42 g, 0.41 mol) in NMP (150 mL) were heated to 170° C. for 18 h. After cooling to room temperature, the reaction mixture was poured into water (200 mL) and stirred for 1 h. The precipitate was filtered, washed with water, and dried to afford 22.7 g of 6-(2,4-difluoro-phenoxy)-1H-quinazoline-2,4-dione (1E).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1>CO.C1COCC1.C(Cl)Cl.[Pd]>[N:13]1([C:11]2[N:12]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)=[O:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(C3=CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(C3CCOCC3)nc(N3CCOCC3)n2)cc1
Reaction time: 3 h
Yield: 24.8 %

Procedure:
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (130 mg, 0.28 mmol) and Pd—C (10%, wet) (113 mg) were suspended in methanol/THF/CH2Cl2 (4:1:1) (30 mL) and hydrogenated (at 1 atm pressure) for 3 h. After completion, the catalyst was removed by filtration over Celite™ and the solvents were removed in vacuo to obtain the crude product, which was purified by semi-prep-HPLC (TFA-method), to give (32 mg=20% yield) of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; MS (ESI) m/z 462.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH:37]1([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>[OH-].[Na+].C(#N)C>[CH:44]1([NH:43][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1.[C:27]1([S:33]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)OCc1ccccc1
Yield: 73.2 %

Procedure:
Nε -benzyloxycarbonyl-L-lysine (8.41 g, 30 mmole) was dissolved in 1N aqueous sodium hydroxide (30 ml), and dioxane (10 ml) solution of benzene sulfonyl chloride (5 30 g, 30 mmole) was added dropwise to the solution while keeping the pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide while cooling with ice and stirring. The mixture was further stirred for 1.5 hours at room temperature and then insoluble matter was removed by filtration. The filtrate was washed with two 100 ml portions of diethyl ether. To the water layer, ethyl acetate (150 ml) was added and the solution was adjusted to pH 1.5 with 1N aqueous hydrochloric acid under vigorous stirring. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the oily residue thus obtained was dissolved in acetonitrile (200 ml), and then dicyclohexylamine (5.43 g, 30 mmole) was added thereto with stirring, and thereby Nα -benzenesulfonyl-Nε -benzyloxycarbonyl-L-lysine dicyclohexylamine salt (13.21 g, 73.2%) was obtained.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4](SC)[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.[CH3:12][OH:13].Cl>CCOCC>[OH:1][C:2]1[N:3]=[C:4]([O:13][CH3:12])[N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: CSc1nc(O)cc(=O)n1C
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COc1nc(O)cc(=O)n1C
Reaction time: 240 h
Yield: 40 %

Procedure:
A mixture of 172 g (1 mol) of 1,6-dihydro-4-hydroxy-1-methyl-2-methylthio-6-oxo-pyrimidine, 700 ml of methanol and 5 ml of a solution of hydrogen chloride in ether was boiled for 10 days under reflux. The reaction mixture was then filtered while still hot and the filtrate is evaporated in vacuo. The residue was triturated with ether and the crystalline product was filtered off. In this way, 71 g (40% of theory) of 1,6-dihydro-4-hydroxy-1-methyl-2-methoxy-6-oxo-pyrimidine were obtained in the form of colorless crystals of melting point 170°-171° C. ##STR11##
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCOCC5)c4)cc23)CC1
Yield: 43.2 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol), morpholine (3.5 ul, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (7.5 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH2:26][OH:27])[C:12]([CH3:25])=[N:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[H-].[Na+].[CH2:30]([O:32][C:33](=[O:38])[C:34](Br)([CH3:36])[CH3:35])[CH3:31]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:30]([O:32][C:33](=[O:38])[C:34]([O:27][CH2:26][C:11]1[C:12]([CH3:25])=[N:13][C:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:10]=1)([CH3:36])[CH3:35])[CH3:31]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2Cl)cc1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)OCc1cc(-c2ccc(Cl)cc2Cl)c(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 500 mg of [5-(2,4-Dichloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 6 ml of DMF were added 242 mg of sodium hydride (60% in mineral oil) at room temperature. After 15 min, 448 mg of tetrabutylammonium iodide and 946 mg of 2-Bromo-2-methyl-propionic acid ethyl ester were added and the reaction mixture was stirred for 16 h at room temperature. After dilution with saturated aqueous sodium hydrogen carbonate solution the reaction mixture was filtered through a chem Elut® cartridge by eluting with ethyl acetate The solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 200 mg.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH2:19][CH2:20][CH3:21])[C:4](=[O:22])[C:3]=1[N+:23]([O-])=O>CO.O.[Pd]>[NH2:23][C:3]1[C:4](=[O:22])[N:5]([CH2:19][CH2:20][CH3:21])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: CCCn1c(=O)c([N+](=O)[O-])c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCn1c(=O)c(N)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 103.7 %

Procedure:
To a solution of 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (200.0 mg) in methanol (10.0 ml) was added palladium hydrate (20.0 mg) and the resulting mixture was stirred at room temperature under catalytic hydrogenation condition for twelve hours. The reaction mixture was degassed and then filtered through Celite (trade mark), and then concentrated under reduced pressure to afford 5-amino-6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (190.0 mg).