Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][C@H:8]([CH2:20][C@H:21]1[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:23](=[O:31])[O:22]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:6])[CH2:2][C:3]([OH:5])=O.CN(C(O[N:40]1N=N[C:42]2C=CC=[CH:46][C:41]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(#N)C>[CH2:25]([C@@H:24]1[C:23](=[O:31])[O:22][C@H:21]1[CH2:20][C@@H:8]([O:7][C:1](=[O:6])[CH2:2][C:3]([NH:40][CH:41]([CH3:46])[CH3:42])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CC(C)N
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)CC(=O)NC(C)C
Yield: 84.9 %

Procedure:
A solution of 33.5 mg of (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl hydrogen malonate (Example N) in 2 ml of acetonitrile was treated with 60 mg of HBTU and 75 mg of isopropylamine. After stirring the reaction mixture was filtered, the filtrate was concentrated and the residue was chromatographed on silica gel with hexane/methylene chloride/ethyl acetate (2:2:1). There were obtained 31.1 mg of (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl-N-isopropylmalonamate, m.p. 59°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](Br)[C:20]#[N:21])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:20]#[N:21]
Reactant: N#CC(Br)c1ccc(Cl)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-trifluoromethylphenol (16.2 g., 0.1 mole) and 4-chlorophenyl-α-bromoacetonitrile (23.05 g., 0.1 mole) in methylene chloride (200 ml.) is added potassium carbonate (27.6 g., 0.2 mole). The reaction mixture is stirred and heated under reflux for six hours. The reaction mixture is then cooled to 25°C. and washed with water (300 ml.). The organic layer is dried over sodium sulfate, filtered and the solvent removed to afford crude (3-trifluoromethylphenoxy)(4-chlorophenyl)acetonitrile which is employed in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([O:13]C)=O.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CCOCC>[OH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[C:11]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)=[O:13]
Reactant: COC(=O)c1sc2ccccc2c1O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1sc2ccccc2c1O
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
A mixture of methyl 3-hydroxy-benzothiophene2-carboxylate (1.04 g; 0.005M) and 3-trifluoromethylaniline (1.61 g; 0.010M) is heated under a nitrogen atmosphere at 170° C. for 90 minutes. and then at 200° C. for 30 minutes. The reaction was cooled at room temperature, taken up in ether and the solid was collected, washed with ether and air dried. The solid was recrystallized from ethyl acetate to give 0.96 g (57% yield) of the title compound; m.p. 205°-208° C. (dec).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc4c(c23)CCCC4)cc1
Product: Fc1ccc(CNc2nc(-n3cccn3)nc3sc4c(c23)CCCC4)cc1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(4-fluorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.00 g), benzyl bromide (0.97 g) potassium carbonate (0.53 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(3-benzyloxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (1.51 g, yield 64%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.B.C1COCC1.Cl.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1ccc(Br)cn1
Yield: 70 %

Procedure:
A solution of 5-bromopicolinonitrile (3.0 g, 16.4 mmol) in BH3.THF (99 mL, 99 mmol, 1M) was heated at reflux temperature for 2 h under N2. MeOH (12 mL) was added slowly followed by 1N HCl (24 mL). The mixture was then refluxed for an additional 7 h. After cooling, the reaction mixture was poured into 10% of K2CO3 (300 mL) and extracted with DCM (3×100 ml). The combined organic layers were concentrated to give crude product which was used in next step without further purification (2.1 g, Yield 70%).
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=[N:17][OH:18])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl[O-].[Na+]>ClCCl>[N:17]1[O:18][CH2:3][CH:2]2[CH2:1][N:4]([C:5]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:14])[CH2:15][C:16]=12
Reactant: C=CCN(CC=NO)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Yield: 75.7 %

Procedure:
A solution of Benzyl N-allyl-N-[2-hydroxyiminoethyl]carbamate (24 g, 96.6 mmol) in dichloromethane (338 mL) is treated drop wise over 10 minutes with a 5% w/w aqueous solution of sodium hypochlorite (106.08 mmol, 143.06 mL). The resultant mixture is stirred at room temperature overnight. The reaction is quenched with a 40% aqueous solution of sodium bisulfite (7 g). The organic layer is separated, dried over magnesium sulfate, and concentrated under vacuum. The crude product is purified over silica gel eluting with 5% ethyl acetate in hexanes to give the title compound (18 g, 75%). ES/MS (m/e): 247 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]([Mg]Br)#[C:19][CH3:20]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:18]#[C:19][CH3:20])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC#C[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC#CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (535 mg) in THF (10 mL) at −78° C. was added 1-propynyl magnesium bromide (8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 3 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)[C:12]=2[CH:40]=1)=[O:6])[CH:2]=[CH2:3].[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:1]([NH:4][C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]2[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[C:28]([C:33]([OH:35])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][CH:26]=3)[C:12]=2[CH:40]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCNC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: C=CCNC(=O)Nc1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-allylaminocarbonylamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2([CH3:30])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1>CO.Cl.O1CCOCC1>[CH3:30][C:17]1([N:14]2[CH2:15][CH2:16][CH:11]([N:3]3[C@@H:4]4[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]4)[CH2:10][C:2]3=[O:1])[CH2:12][CH2:13]2)[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(N2CCC(N3C(=O)C[C@H]4CCCC[C@@H]43)CC2)CCNCC1

Procedure:
A solution of tert-butyl 4-[4-[(3aR,7aS)-2-oxo-3a,4,5,6,7,7a-hexahydro-3H-indol-1-yl]-1-piperidyl]-4-methyl-piperidine-1-carboxylate in MeOH (14 mL) and 4M HCl in dioxane (5 mL) was stirred at room temperature overnight. Concentrated in vacuo and the residue was purified by preparative LC/MS (high pH) to provide the title compound as a colorless oil (0.41 g). MS (M+1): 320.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38](Cl)=[O:39]>>[Cl:32][C:33]1[C:34]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([F:46])[C:35]=2[S:36][C:37]=1[C:38]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:11][CH2:12]1)=[O:39]
Reactant: COc1ccc(-c2cccnc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2cccnc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 173 (320 mg, 0.75 mmol) is treated with acid chloride 8 (221 mg, 0.83 mmol) using Method D to give the title compound.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:35])[CH2:32][O:33][CH3:34]>>[CH3:34][O:33][CH2:32][C:31]1[N:35]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: COCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: COCc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
100 mg (0.25 mmol) of the compound from Example 44A and 31 mg (0.30 mmol) of N′-hydroxy-2-methoxyethanimidamide (J. Med. Chem., 1997, 40, 8, 1230-1246) were reacted according to the General Method 1. Yield: 19 mg (16% of theory).
Reaction SMILES: [N:1]1([CH2:7][C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCCCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CCN(C[C@@H]2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the (S)-tert-butyl 3-(piperidin-1-ylmethyl)piperidine-1-carboxylate isolated above in 200 μL DCM was slowly added 2 mL TFA and the resulting solution stirred for 30 min at 25° C. The solvent was evaporated and the crude product was used directly in the next reaction without further purification. (For example, reaction with Intermediate A5 in Specific Scheme 5)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:29](O)/[CH:30]=[CH:31]\[CH2:32][OH:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:29][CH:30]=[CH:31][CH2:32][OH:33])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OC/C=C\CO
Product: O=C1c2ccccc2C(OCC=CCO)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 57.9 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis-butenediol (445 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a yellow oil (272 mg, 58%). 1H NMR (300 MHz, CDCl3): 8.04-8.00 (m, 2H, O2N—C—CH), 7.93-7.91 (m, 1H, C(O)═C═CH), 7.57-7.51 (m, 2H, Ar—H), 7.39-7.36 (m, 2H, Ar—H), 7.23-7.12 (m, 5H, Ar—H), 5.62-5.53 (m, 1H, OCH2Cl), 5.35-5.26 (m, 1H, OCH2CH), 4.64 and 4.26 (dd: AB, J=15.0 Hz, 2H, N—CH2), 3.79 (d, J=6.6 Hz, HO—CH2), 3.48-3.29 (m, 2H, O—CH2). 13C NMR (75 MHz, CDCl3): 168.17, 147.45, 145.07, 144.60, 136.86, 134.98, 133.07, 132.00, 131.44, 130.24, 130.02, 128.71, 127.99, 126.79, 123.89, 123.35, 95.00, 59.20, 58.48, 42.57. m/z (ES): 465 [M+H]+. Anal.: calc. for C25H21ClN2O5: C, 64.59; H, 4.55; N, 6.02. Found: C, 64.39; H, 4.67; N, 5.67.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([NH2:13])[CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[N:26]=[C:25]([N:27]([C:29]2[C:37]3[O:36][CH2:35][O:34][C:33]=3[CH:32]=[CH:31][C:30]=2[Cl:38])[CH3:28])[CH:24]=[CH:23][N:22]=1>>[Cl:38][C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][O:36][C:37]=2[C:29]=1[N:27]([CH3:28])[C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:13][C:11]2[CH:10]=[C:9]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:12]=2)[N:26]=1
Reactant: Nc1cc(N2CCOCC2)nc(N2CCOCC2)c1
Reactant: CN(c1ccnc(Cl)n1)c1c(Cl)ccc2c1OCO2
Product: CN(c1ccnc(Nc2cc(N3CCOCC3)nc(N3CCOCC3)c2)n1)c1c(Cl)ccc2c1OCO2
Yield: 25.3 %

Procedure:
2,6-Dimorpholinopyridin-4-amine (160 mg, 0.60 mmol) and 2-chloro-N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N-methylpyrimidin-4-amine (180 mg, 0.60 mmol) were reacted according to the procedure in Example 1 to give N4-(5-chlorobenzo[d][1,3]dioxol-4-yl)-N2-(2,6-dimorpholinopyridin-4-yl)-N4-methylpyrimidine-2,4-diamine (80 mg, 25.2%) as a pale yellow foam. NMR Spectrum (CDCl3) 3.23-3.58 (m, 11H), 3.72-3.90 (m, 8H), 5.65 (s, 1H), 6.03 (s, 2H), 6.50 (s, 2H), 6.79 (d, 1H), 6.99 (d, 1H), 7.17 (s, 1H), 7.90 (s, 1H); Mass spectrum: MH+ 526.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.CC[N:18]([CH:22]([CH3:24])C)[CH:19]([CH3:21])C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCC1>CN(C=O)C>[Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:18]1[CH2:19][CH2:21][CH2:24][CH2:22]1)=[O:9]
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCC1
Temperature: 25 °C
Yield: 252.4 %

Procedure:
2-Chloro-5-phenyl-thiophene-3-carboxylic acid (28 mg, 0.11 mmol) was dissolved in DMF (1 mL). DIPEA (0.22 mmol), HATU (0.11 mmol) and pyrrolidine (0.11 mmol) were added and the reaction mixture stirred at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic solution was separated and dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by preparative HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (81 mg). LCMS m/z 292.10 [M+H]+ R.T.=11.27 mins (Analytical Method 1)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([NH:11][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=2)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1cccnc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1c(O)cccc1C(=O)O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Thionyl chloride (10 mL) was added to nicotinic acid (370 mg, 3 mmol) and the mixture was stirred at reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to obtain nicotinoyl chloride. 3-Hydroxyanthranilic acid (153 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then nicotinoyl chloride (420 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min and then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20: to 5:1) to get 3-hydroxy-2-(nicotinamido)benzoic acid as a solid (210 mg, yield 81%). LC-MS (ESI) m/z 259 [M+1]+.
Reaction SMILES: [C:1]([O:8]N=C(C1C=CC=CC=1)C#N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24]/[CH:25]=[CH:26]/[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][NH2:32]>C1COCC1>[C:1]([NH:32][CH2:31][CH2:30][CH2:29][N:28]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8])[CH2:27]/[CH:26]=[CH:25]/[CH2:24][N:23]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:8])[CH2:22][CH2:21][CH2:20][NH:19][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:8]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCCCNC/C=C/CNCCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of 25.86 g (105 mmol) of 2-(BOC-oxyimino)-2-phenylacetonitrile (Fluka, Switzerland) in 70 ml of THF is added dropwise over a period of 2 h, with stirring, to a solution, cooled to 5° C., of 5.01 g (25 mmol) of (E)-1,5,10,14-tetraazatetradec-7-ene in 50 ml of THF. The reaction mixture is stirred for a further 16 h at room temperature and is then concentrated by evaporation in vacuo. The residue is purified by flash chromatography, over silica gel having an average particle size of 0.04-0.063 mm, using ethyl acetate-hexane (1:3). Concentration of the product-containing fractions by evaporation yields the resinous title compound, Rf value=0.33 (silica gel/ethyl acetate:hexane (1:1)).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[N:21]([CH2:25][CH3:26])[N:20]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].C1COCC1.C(O)(C)C>O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([CH3:24])[N:21]([CH2:25][CH3:26])[N:20]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:41])([CH3:40])[CH3:42]
Reactant: CCn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CCn1nc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.6 %

Procedure:
A mixture of 118c (80 mg, 0.13 mmol), lithium hydroxide (13 mg, 0.53 mmol), THF (6 mL), i-propanol (4 mL) and water (2 mL) was stirred at room temperature for 0.5 h. The mixture was concentrated under reduced pressure and diluted with water (5 mL). It was then extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 118 (20 mg, 26%) as a white solid. MS-ESI: [M+H]+ 558.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.50 (d, J=5.0 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 5.88 (s, 1H), 4.92 (t, J=5.0 Hz 1H), 4.46-4.45 (m, 2H), 3.91 (q, J=7.5 Hz, 2H), 3.59 (s, 3H), 2.19 (s, 3H), 1.40 (s, 9H), 1.27 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([O:7][C:8]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([O:7][C:8](=[O:9])[NH:10][C@H:11]2[C:12](=[O:14])[O:17][C@H:15]2[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](O)[C@@H](NC(=O)OC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OC1CCCCC1
Temperature: 0 °C
Reaction time: 15 h
Yield: 35.3 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-2-(cyclohexoxycarbonylamino)-3-hydroxy-butanoic acid (0.3 g, 1.22 mmol) in dry CH2Cl2 (16 mL), Et3N (0.51 mL, 3.66 mmol) and subsequently TBTU (0.47 g, 1.46 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h at rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.098 g, 36%) as white solid. MS (ESI) m/z: 228 [M−H]+; (ESI) m/z: 226 [M−H]−. 1H NMR (DMSO-d6): δ 1.14-1.42 (m, 5H), 1.34 (d, J=6.3 Hz, 3H), 1.44-1.55 (m, 1H), 1.61-1.72 (m, 2H), 1.76-1.89 (m, 2H), 4.47-4.59 (m, 1H), 4.84 (dq, J=6.3 Hz, 1H), 5.40 (dd, J=6.2, 9.3 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H).