Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CN1[CH:14]=[CH:13][C:12](=[O:15])N(C)C1=O>CCO>[N:2]1[N:3]2[CH:14]=[CH:13][C:12]([OH:15])=[N:7][C:4]2=[CH:5][CH:6]=1
Reactant: Cn1ccc(=O)n(C)c1=O
Reactant: Nc1cc[nH]n1
Agent: [Na]
Solvent: CCO
Product: Oc1ccn2nccc2n1
Yield: 52.8 %

Procedure:
To a solution of dry EtOH (500 mL) was added sodium (22.1 g, 481 mmol) under a cold water bath. After complete dissolution, 1H-pyrazol-3-amine (40.0 g, 481 mmol) and 1,3-dimethylpyrimidine-2,4(1H,3H)-dione (101 g, 722 mmol) were added. The reaction mixture was heated at reflux for 4 hours. After cooling, the white solid was collected by filtration, washed with cold EtOH and dried under vacuum. The crude solid was suspended in minimum amount of water and the pH of the solution was adjusted to 5 by dropwise addition of acetic acid. The precipitated solid was collected by filtration, re-dissolved in MeOH and concentrated by rotary evaporation to azeotrope any remaining water to afford pyrazolo[1,5-a]pyrimidin-5-ol (34.3 g, 53%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:28][N:25]1[CH2:24][CH2:23][N:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:34]5[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=5)[CH:3]=4)[C:8](=[O:12])[NH:7][C:6]3=[O:13])=[CH:17][CH:18]=2)[CH2:27][CH2:26]1
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5ccc(C#N)cc5)cc43)cc2)CC1
Temperature: 180 °C
Yield: 29.5 %

Procedure:
To a suspension of 6-bromo-4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione (221 mg, 0.5 mmol) in N,N-dimethylformamide (5 mL) is added 4-cyanophenylboronic acid (88 mg, 0.6 mmol), followed by 300 □L of 2M aqueous cesium carbonate and tetrakis triphenylphosphine palladium (30 mg, 0.06 mmol). The reaction mixture is subjected to microwave heating at 180° C. for 300 seconds. The reaction mixture is then diluted with N,N-dimethylformamide and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield 4-(4-{[4-(4-Methyl-piperazin-1-yl)-phenylamino]-methylene}-1,3-dioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-benzonitrile (68.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([Sn](CCCC)(CCCC)CCCC)=[C:6]([O:23][CH3:24])[CH:5]=1.[CH2:26]([O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=[O:39])=[C:36](Br)[CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([C:36]2[CH:35]=[C:34]([O:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([O:42][CH3:43])=[CH:40][C:37]=2[CH:38]=[O:39])=[C:6]([O:23][CH3:24])[CH:5]=1)=[O:25]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(=O)OC)cc1OC
Reactant: COc1cc(C=O)c(Br)cc1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2cc(OCc3ccccc3)c(OC)cc2C=O)c(OC)c1
Yield: 54.3 %

Procedure:
To a stirred solution of 3-methoxy-4-tributylstannanyl-benzoic acid methyl ester (16g, 35 mmol) and 4-benzyloxy-2-bromo-5-methoxy-benzaldehyde (9.4 g, 29 mmol) in acetonitrile (150 mL) were added CuI (5.5 g, 29 mmol) and Pd(dppf)Cl2 (4.2 g, 6 mmol). The resulting mixture was refluxed for 14 h under argon and concentrated. The residue was purified by column chromatography (4:1 hexane/EtOAc) to provide 5′-benzyloxy-2′-formyl-2,4′-dimethoxy-biphenyl-4-carboxylic acid methyl ester (6.4 g, 54%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C@@H:10](NC(=O)OCC1C=CC=CC=1)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.FC(F)(F)S([N:44]=[C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=O)=O.O>O1CCCC1.[Pd]>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:31])[C@@H:10]([NH:44][C:45]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[N:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:11][NH:12][C:13]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:19]
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)c1N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of 2-benzyl 1-tert-butyl {(2S)-3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxo-1,2-propanediyl}biscarbamate (1.58 g) in tetrahydrofuran (28 ml) was treated with 10% palladium on carbon (0.75 g) under a hydrogen atmosphere for 2 hours at room temperature. After the catalyst was filtered off, the filtrate was concentrated in vacuo to give a crude oil, which was dissolved in tetrahydrofuran (28 ml). To the solution were added triethylamine (2.04 ml) and di-tert-butyl ({[(trifluoromethyl)sulfonyl]imino}methylene)biscarbamate (2.86 g) successively at room temperature. The mixture was stirred at room temperature overnight. To the reaction mixture was added water to quench the reaction. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give di-tert-butyl {[((1S)-2-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}-2-oxoethyl)amino]methylylidene}biscarbamate (1.53 g) as an amorphous solid.
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=1)=O)[NH2:2].[CH:22]1([NH:25][CH:26]=O)[CH2:24][CH2:23]1.C1(N)CC1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:22]1([N:25]2[CH:26]=[N:2][N:1]=[C:3]2[C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:23]1
Reactant: O=CNC1CC1
Reactant: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
To a sealable flask containing benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (1.97 g, 6.89 mmol, 1.0 eq) was added N-cyclopropyl formamide (1.8 mL, 20.7 mmol, 3.0 eq), cyclopropylamine (1.4 mL, 20.7 mmol, 3.0 eq), toluene (0.2 M), and trifluoracetic acid (0.511 mL, 6.89 mmol, 1.0 eq). The flask was sealed and heated to 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography (Rf=0.44 in 10% methanol/ethyl acetate, gradient flash: 3%→10% methanol in ethyl acetate). The product, which consisted of a mixture of the desired compound with cyclopropyl formamide, was suspended in acetonitrile, sonicated, and the resultant suspension filtered to provide benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (680 mg).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:45])[C@@H:7]([NH:35][S:36]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:38])=[O:37])[CH2:8][NH:9][C:10]([C:12]1[O:16][N:15]=[C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[CH:13]=1)=[O:11].OS([O-])(=O)=O.[Na+]>C1COCC1>[C:28]([N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:14]2[CH:13]=[C:12]([C:10]([NH:9][CH2:8][C@H:7]([NH:35][S:36]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)(=[O:38])=[O:37])[C:6]([OH:45])=[O:5])=[O:11])[O:16][N:15]=2)[CH2:23][CH2:24]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(OCCCCC2CCN(C(=O)OC(C)(C)C)CC2)no1)NS(=O)(=O)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCOc2cc(C(=O)NC[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)on2)CC1
Yield: 99.2 %

Procedure:
A solution of LiOH.H2O (35 mg, 0.87 mmol, 4-6 (176 mg, 0.29 mmol), and 20% aq. THF (10 mL) was stirred at ambient temperature for 1 h. The reaction mixture was acidified with 1M NaHSO4 and extracted with EtOAc (3×). The combined extracts were dried (MgSO4) and concentrated to give 4-7 (171 mg) as a foam. Rf 0.73 (silica, 9:0.5:0.5 CH2Cl2 /CH3OH/AcOH). ##STR49## 3-[4-(Piperidin-4-yl)butyloxy]isoxazole-5-carbonyl-2(S)-phenylsulfonylamino-β-alanine (4-8)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[NH2:7][C:6]1[CH:8]=[C:2]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of 5-fluoro-2-nitroaniline (10 g, 64.1 mmol) in DMF (65 mL) was added tert-butyl-piperazine carboxylate (13.1 g, 70.5 mmol) and K3PO4 (13.3 g, 96.2 mmol). The reaction mixture was stirred at 100° C. overnight. After adding 100 ml H2O into the solution, the precipitated yellow solid was filtered under vacuum then dried in vacuo to afford tert-butyl 4-(3-amino-4-nitrophenyl)piperazine-1-carboxylate as yellow solid (15 g, yield: 82%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1.[F-].[K+].Cl>CN(C)C=O.O>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:17][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)C2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)C3)nc1

Procedure:
6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg), 2-chloro-5-nitropyridine (21 mg) and potassium fluoride (23 mg) in dry dimethylformamide were heated at 120° C. until disappearance of the starting material. Water and 1 N HCl were added and the mixture extracted with ethyl acetate. Ethyl acetate was washed with brine and water, dried and evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:24])(=[O:23])[NH:14][C:15]2[N:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=2)=[CH:9][CH:8]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:2]([Cl:1])[C:3]=1[CH:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH:14][C:15]2[N:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[N:20]=2)(=[O:23])=[O:24])=[CH:9][CH:8]=1)[OH:5]
Reactant: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(NS(=O)(=O)c2ccc(NC(O)c3c(Cl)cccc3Cl)cc2)n1
Reaction time: 8 h
Yield: 18 %

Procedure:
11 mg (0.02 mmol) of 2,6-dichloro-N-[4-(4,6-dimethylpyrimidin-2-yl-sulfamoyl)-phenyl]-benzamide was dissolved in 2 ml tetrahydrofurane. Lithium aluminium hydride (6 mg, 0.16 mmol) was added to the reaction mixture under nitrogen atmosphere and solution was stirred overnight. The reaction mixture was filtered, evaporated to dryness and purified by on silica using gradient elution (chloroform to 4% methanol in chloroform) to obtain the title compound with a yield of 18%. MS (ESI+): m/z 475 (M+Na)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.[CH:17]1([N:22]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([N:22]([CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[OH:29])=[CH:26][CH:25]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=Cc1ccc(C(=O)N(C2CCCC2)C2CCCC2)cc1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 8 using 4-bromoveratrole (1.29 mL, 10 mmol), n-butyl lithium (6.25 mL of 1.6 M solution in hexane), terephthalaldehydic acid N,N-dicyclopentyl amide (Example 29) (2.6 g, 9.1 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane to give the title compound as an oil that crystallized under ethyl ether: m. pt. 137-138° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1.Cl>CN(C)C=O.O>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.5 %

Procedure:
A solution of benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (188 mg, 0.42 mmol) and 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (94 mg, 0.28 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (150 μL, 0.85 mmol) and 2-aminothiazole (42.5 mg, 0.42 mmol). The mixture was stirred at 25° C. for 48 h. At this time, the reaction mixture was poured into cold water (25 mL) containing a 1N aqueous hydrochloric acid solution (50 mL) and extracted into ethyl acetate (2×75 mL) and diethyl ether (1×25 mL). The combined organic layers were then washed with water (2×75 mL) and a saturated aqueous sodium chloride solution (3×75 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide (50.5 mg, 43.1%) as a clear oil: FAB-HRMS m/e calcd for C19H21F3N2OS2 (M+H)+ 415.1125, found 415.1123.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:25])([CH3:24])[C:18]=3[CH:26]=2)=[CH:4][C:3]=1[CH3:27].[OH:28]O.O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]3[NH:22][C:21](=[O:23])[O:20][C:19]([CH3:24])([CH3:25])[C:18]=3[CH:26]=2)=[O:28])=[CH:4][C:3]=1[CH3:27]
Reactant: OO
Reactant: Cc1cc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(S(=O)CCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 9.2 gm (0.02 mol) of 6-[4-(4-bromo-3-methyl-phenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one is dissolved in 100 ml of glacial acetic acid, and 2 ml (0.02 mol) of 30% hydrogen peroxide are added. The mixture is stirred for three hours at ambient temperature, poured onto 400 ml of water, and extracted three times with ethyl acetate. The organic phase is washed with water and dried with sodium sulfate, and the ethyl acetate is distilled off. The solid residue is recrystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]>O1CCCC1.CO.[Pd]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]
Reactant: Cc1cc(/C=C/C(=O)O)ccc1C#N
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CCC(=O)O)ccc1C#N
Reaction time: 8 h
Yield: 99.9 %

Procedure:
5.15 g (E)-3-(4-Cyano-3-methyl-phenyl)-acrylic acid were dissolved in a mixture of 250 ml tetrahydrofuran and 125 ml methanol. 510 mg palladium on charcoal (10%) were added and the reaction mixture was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off over a celite pad. The solvent was removed in vacuo to obtain 5.2 g 3-(4-Cyano-3-methyl-phenyl)-propionic acid as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH:29]1[CH2:34][CH2:33][CH:32]([C:35]#[N:36])[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][N:29]2[CH2:34][CH2:33][CH:32]([C:35]#[N:36])[CH2:31][CH2:30]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: N#CC1CCNCC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C#N)CC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with piperidine-4-carbonitrile via General Procedure E to give 21.9 mg of 291 following reverse phase purification. MS (Q1) 472.2 (M)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15]>N1C=CC=CC=1>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:15]
Reactant: COCC(=O)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: COCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminobenzothiazole (4.5 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is dissolved in chloroform and the organic layer is washed with water and then with a saturated saline. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The resulting solids are recrystallized from ethanol/water to give the title compound (5.2 g) having the following physical properties.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[O:6]1[C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=[CH:7]1.O.CN(C)[CH:31]=[O:32]>>[CH:31]([C:7]1[O:6][C:10]2[CH2:11][N:12]([C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1)=[O:32]
Reactant: O=C(CCCCCc1ccccc1)N1CCc2ccoc2C1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cc2c(o1)CN(C(=O)CCCCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 30 ml of N,N-dimethylformamide, 0.33 ml (3.6 mmol) of phosphorus oxychloride was added under ice-cooling, followed by stirring at room temperature for 0.5 hours. To this mixture, a solution of 1.064 g (3.578 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-phenylhexan-1-one in 20 ml of N,N-dimethylformamide was added, followed by overnight stirring at room temperature. After water was added, the reaction mixture was extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel flush column chromatography (hexane/ethyl acetate=2/1 to 1/1) to yield the desired product.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11](Cl)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C=O)C>O>[CH2:1]([C:8]1[S:12][C:11]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(Cl)sc2Cc2ccccc2)cc1
Reactant: C1CNCCN1
Agent: [Li]O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(N3CCNCC3)sc2Cc2ccccc2)cc1
Temperature: 100 °C
Yield: 69.5 %

Procedure:
To 25 ml eggplant-shaped bottle were added 1.30 g (4.12 mmol) 5-benzyl-2-chloro-4-(4-methoxy-phenyl)-thiazole prepared in the step 1 of Example 70, 0.35 g (8.24 mmol) LiOH.H2O, 20 mg KI, 1.77 g (20.6 mmol) piperazine, 5 ml DMF and 0.5 ml water. The mixture was stirred until homogeneous, heated to 100° C., stirred for 12 hours, added 20 ml water, and extracted with ethyl acetate three 3×10 ml. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a thick crude product, which was purified under a reduced pressure by silica gel column chromatography eluted with dichloromethane and methanol at a ratio 10:1-5:1 (V:V) to give a 1.05 g oily and thick product in a yield of 69.5%, 1H-NMR (CDCl3, 400 MHz) δ: 2.99 (4H, t, J=5.2 Hz, 2×CH2), 3.46 (4H, t, J=5.2 Hz, 2×CH2), 3.82 (3H, s, OCH3), 4.12 (2H, s, CH2), 6.90 (2H, d, J=8.80 Hz, ArH), 7.18˜7.35 (5H, m, ArH), 7.53 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 365.0 (M+, 86), 323.0 (28), 309.0 (100), 296.0 (49); HREI-MS Calcd. for C21H23N3OS: 365.1562. found: 365.1564.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][CH2:14][C:15]([N:17]1[CH2:25][CH2:24][C:19]2(OCC[O:20]2)[CH2:18]1)=[O:16].Cl(O)(=O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:13][CH2:14][C:15]([N:17]1[CH2:25][CH2:24][C:19](=[O:20])[CH2:18]1)=[O:16]
Reactant: O=C(CNc1ncnc2cc(Cl)c(Cl)cc12)N1CCC2(C1)OCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: O=C1CCN(C(=O)CNc2ncnc3cc(Cl)c(Cl)cc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a stirring 0° C. solution of 2-(6,7-dichloroquinazolin-4-ylamino)-1-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)ethanone (0.603 g, 1.57 mmol) (prepared by general procedures G, F, M) in DCM (15 mL) was slowly added perchloric acid (0.406 mL, 4.72 mmol). The mixture was allowed to warm to room temperature and stirred for about 1 hour. The solvent was decanted and discarded. The remaining solid was washed with aqueous sodium carbonate (10 mL) and water (10 mL) and then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 1-(2-(6,7-dichloroquinazolin-4-ylamino)acetyl)pyrrolidin-3-one (0.493 g, 1.45 mmol) as white solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method b) Rt 1.62 min; m/z: (M+H)+ 339.