Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][S:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][S:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CSCCN
Agent: I
Solvent: CCO
Product: CSCCNC(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (1.7 g) prepared as described in Example 166, 2-methylthioethylamine (1.8 g) and ethanol (25 ml) was heated at 90°-95° C. for 22 hours to give 1-(2-methylthioethyl)-2-(2-morpholinophenyl)guanidine (m.p. 115°-116° C.) which was recrystallised from hexane.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F-].[K+]>C1COCC1>[Cl:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1ccccc1Br
Reactant: OB(O)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccccc1
Yield: 93.3 %

Procedure:
2-Bromochlorobenzene (96 mg, 0.50 mmol) reacted with phenylboronic acid (79 mg, 0.65 mmol) using 1/2 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in THF at room temperature to give the title compound (88 mg, 93%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.40-7.19 (m, 9H). 13C{1H}-NMR (100 MHz, CDCl3): δ 140.45, 139.33, 132.43, 131.32, 129.88, 129.39, 128.47, 127.99, 127.55, 126.77. GC/MS(EI):188 (M+), 190, 152, 76.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH2:13])=[CH:10][CH:11]=2)[N:6]=1.C(N(CC)CC)C.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:8][C:9]([CH2:12][NH:13][C:26](=[O:27])[CH2:25][O:24][C:21](=[O:23])[CH3:22])=[CH:10][CH:11]=2)[N:6]=1
Reactant: NCc1ccc(-c2csc(N)n2)s1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)NCc1ccc(-c2csc(N)n2)s1
Temperature: 25 °C

Procedure:
To a suspension of 2-amino-4-(5-aminomethyl-2-thienyl) thiazole in 150 ml of chloroform is added 10 ml of triethylamine, and 3.1 g of acetoxyacetylchloride is added dropwise with stirring at room temperature (10°-35° C.). The whole mixture is stirred at room temperature for an hour, and then washed with water. The organic layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 2-amino-4-(5-acetoxyacetylaminomethyl-2-thienyl) thiazole, melting at 149°-150° C. The corresponding maleate melts at 153°-154° C. with decomposition.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Cl.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[ClH:1].[CH2:10]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCO
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: CCCCCCOC(=O)[C@@H](N)CS

Procedure:
L-Cysteine hydrochloride (78.5 g) is added to 150 ml of hexanol saturated with dry HCl gas. The mixture is heated under reflux overnight. The solution is evaporated to about half of the total volume, and then ethyl ether (150 ml) is added. The solution gives crystals when it is cooled. The crystals are filtered and are then recrystallized from ethyl acetate; yield 45 g; mp 89°-90° C.; IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ9.2-8.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH--), 4.3 (t, 2, --OCH2 --), 3.4 (b, 2, CH2S--), 1.0-3.0 (m, 8), 1.0 (t, 3--, CH3).
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].O.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>CO>[CH3:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[N:1][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: CN1CCCCC1=N
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCCCC1=NC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.60 g.; 0.068 mole) is converted to free base by adding 7 ml. of NaOH (50%) to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth. A benzene solution of 12.73 g. (0.068 mole) of p-trifluoromethylphenylisocyanate [prepared according to Inukai and Maki, Kogyo Kagaku Zasshi, 67 (5) 807-9 (1964] is added to the above solution slowly. After 4 hours of stirring at room temperature, the benzene is evaporated in vacuo to give a solid residue. Repeated recrystallizatons of the solid from methanol yields the pure product, 1-(1-methyl-2-piperidylidene)-3-(4-trifluoromethylphenyl)urea, m.p. = 154°-155° C.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[C:2]#[CH:3].[OH:10][CH2:11][C:12]1([CH2:16][CH2:17][CH3:18])[CH2:15]O[CH2:13]1>>[CH2:16]([C:12]12[CH2:11][O:10][C:7]([CH2:6][CH2:5][O:4][CH2:1][C:2]#[CH:3])([O:9][CH2:15]1)[O:8][CH2:13]2)[CH2:17][CH3:18]
Reactant: C#CCOCCC(=O)O
Reactant: CCCC1(CO)COC1
Product: C#CCOCCC12OCC(CCC)(CO1)CO2

Procedure:
4-n-Propyl-1-[2-(prop-2-ynyloxy)ethyl]-2,6,7-trioxabicyclo[2.2.2] octane was prepared from 3-(prop-2-ynyloxy)propionic acid and 3-hydroxymethyl-3-n-propyloxetane using methodology described in Example I.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)[CH:4]=[N:3]1
Reactant: Cn1cc(C=O)cn1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Cn1cc(-c2c3nc(c(-c4cnn(C)c4)c4ccc([nH]4)c(-c4cnn(C)c4)c4nc(c(-c5cnn(C)c5)c5ccc2[nH]5)C=C4)C=C3)cn1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To a refluxing solution of propionic acid (200 mL) and 1-methylpyrazole-4-carboxaldehyde (48, 0.92 g, 8.32 mmol), prepared according to literature procedure (Finar, I. L.; Lord, G. H. J. Chem. Soc. 1957, 3314-3315), was added pyrrole (0.63 mL, 8.32 mmol). The reaction was covered with foil and was heated under reflux for 3.5 h. Upon cooling the reaction mixture was exposed to air overnight. The propionic acid was then removed by vacuum distillation. The crude residue was dissolved in 5% MeOH/CH2Cl2, then adsorbed onto silica gel (5.3 g). Purification by column chromatography (5% MeOH/CH2Cl2) provided porphyrin 49 as a purple solid (231 mg, 17.5%): 1H NMR (300 MHz, DMSO-d6) δ−2.74 (s, 2H), 4.28 (s, 12H), 8.31 (s, 4H), 8.67 (s, 4H), 9.16 (s, 8H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Product: Cc1ccc(Oc2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-methylphenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-methylphenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[C:15]([F:16])=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[F:17])=[CH:5][C:4]([CH3:18])=[N:3]1.[I:19]N1C(=O)CCC1=O.O>C(#N)C>[F:17][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([F:16])[C:8]=1[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[C:5]=1[I:19])[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Oc2c(F)cc(C#N)cc2F)n(C)n1
Solvent: O
Solvent: CC#N
Product: Cc1nn(C)c(Oc2c(F)cc(C#N)cc2F)c1I

Procedure:
A solution of 4-[(1,3-dimethyl-1H-pyrazol-5-yl)oxy]-3,5-difluorobenzonitrile (i.e. the product of Step A) (1.38 g, 5.5 mmol) in acetonitrile (20 mL) was stirred at ambient temperature, and N-iodosuccinimide (1.35 g, 6.0 mmol) was added in one portion. The reaction mixture was heated at reflux for 2 h, cooled, and then poured into water (40 mL). The resulting mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with water (20 mL) and saturated aqueous NaHCO3 solution (20 mL), dried over MgSO4, and concentrated under reduced pressure to give the title compound as a tan solid (2.1 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:27]3[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-4-(4-isobutylpiperazin-1-yl)-3-nitropyridin-2-amine (0.039 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 1 to 2.5% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.013 g, 26%); 1H-NMR (500 MHz, DMSO-d6) 0.91 (d, J=6.55 Hz, 6H, CH(CH3)2), 1.82 (m, 1H, CH(CH3)2), 2.12 (d, J=7.35 Hz, 2H, N—CH2), 2.56 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.63 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.01 Hz, 2H) and 8.02 (d, J=8.87 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.17 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=1[NH2:12].Br[C:14]1[S:15][C:16]([Br:20])=[C:17]([CH3:19])N=1>>[Br:20][C:16]1[S:15][C:14]2=[N:12][C:4]3[C:5]([C:6](=[O:7])[N:8]2[C:17]=1[CH3:19])=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1]
Reactant: COc1cccc(C(N)=O)c1N
Reactant: Cc1nc(Br)sc1Br
Product: COc1cccc2c(=O)n3c(C)c(Br)sc3nc12
Yield: 77.7 %

Procedure:
4.8 g of 3-methoxyanthranilamide and 7.5 g of 2,5-dibromo-4-methylthiazole were stirred for 12 hours at 140° C. After working up in the conventional manner there was obtained 7.3 g (77%) of the above compound; m.p. 198°-199° C.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+]>[CH2:12]([N:19]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 140 °C

Procedure:
N-Benzylphthalimide is prepared as described in Example 2, starting with 10 g of phthalic anhydride, 7.3 cm3 of benzylamine and a catalytic amount of para-toluenesulfonic acid in 100 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 3 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is taken up in 100 cm3 of saturated aqueous sodium bicarbonate solution and the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 10.3 g of N-benzylphthalimide are thus obtained in the form of a white powder. (Rf=0.44, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [Si]([C:8]#[C:9][C:10]1[S:14][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:17]=2)=[C:12]([C:29]([NH2:31])=[O:30])[CH:11]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:9]([C:10]1[S:14][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:17]=2)=[C:12]([C:29]([NH2:31])=[O:30])[CH:11]=1)#[CH:8]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C(N)=O)c(Nc2cccc(CN3CCOCC3)n2)s1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-{[tert-butyl(dimethyl)silyl]ethynyl}-2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}thiophene-3-carboxamide (435 mg, 0.95 mmol) in THF (15 mL) was added TBAF (1.0 M in THF, 2.38 mL, 2.38 mmol), and the reaction was stirred at room temperature for 6 h. The solution was diluted with water and extracted with EtOAc (2×). The organic extracts were dried over magnesium sulfate, filtered, combined with silica gel and evaporated. Flash chromatography (dry load, 0-10% MeOH/EtOAc) provided the title compound as a gray solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:10])[C:6](Cl)=[N:7][OH:8])[CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:20])/[CH:15]=[CH:16]/N(C)C)[CH3:12].C(OCC)(=O)C>C1COCC1>[CH2:11]([O:13][C:14]([C:15]1[C:6]([C:5](=[O:10])[NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:7][O:8][CH:16]=1)=[O:20])[CH3:12]
Reactant: O=C(NC1CC1)C(Cl)=NO
Reactant: CCOC(=O)/C=C/N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1conc1C(=O)NC1CC1
Temperature: 75 °C

Procedure:
A mixture of N-cyclopropyl-2-chloro-2-hydroxyimino-acetamide (2 g, 12.3 mmol) and (E)-3-(dimethylamino)-acrylic acid ethyl ester (1.76 ml, 12.3 mmol) in THF (25 ml) was heated at 75° C. for 2 h. The reaction was then cooled to r.t., poured into 100 mL ethyl acetate and extracted with 1 M HCl. The aqueous layers were back-extracted with ethyl acetate. The organic phase was washed with water and brine, dried and evaporated. The product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light yellow solid (1.6 g, 58%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:18])[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:11]2[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(O)(C)(C)C.CCCCCCC.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:22][S:19]([C:12]1[C:13]([CH3:18])=[N:14][C:15]2[C:10]([C:11]=1[N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:9][C:8]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[CH:17][CH:16]=2)(=[O:21])=[O:20]
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(Br)cc2c(N2CCOCC2)c1S(C)(=O)=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCCCCCC
Product: Cc1nc2ccc(N3CCCCC3)cc2c(N2CCOCC2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 79 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (11 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (10 mg, 0.021 mmol) and cesium carbonate (1.3 g, 3.99 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-morpholin-4-yl-quinoline (compound of example 6) (200 mg, 0.52 mmol) in tert.-butanol (10 ml) was added, followed by piperidine (0.053 g, 0.62 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate 80:20 to give a yellow solid (160 mg, 79%). MS: m/z=390 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23](=[O:24])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C=Nc1ccccc1
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)Nc2ccccc2)cc1

Procedure:
6-(4-Aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.5 g) was reacted with phenyl isocyanate (0.88 ml) in the same manner as Example 6 to give 6-[4-(3-phenylureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.26 g).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH2:25]([O:27][C:28](=[O:35])[CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26]>CS(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([N:31]3[CH2:32][CH2:33][CH2:34][CH:29]([C:28]([O:27][CH2:25][CH3:26])=[O:35])[CH2:30]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CS(C)=O
Product: CCOC(=O)C1CCCN(C(=O)CCn2cnc3c(=O)[nH]cnc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was placed into a 10 ml round bottom flask with 2 ml dry dimethylsulfoxide and a magnetic stirring bar. 150 mg of (+ -)-ethylnipecotate was added to the solution. The solution immediately turned green and was stirred at room temperature (25°) for two hours. The dimethylsulfoxide was removed under reduced pressure with gentle heating. 10 ml of ether was added to the yellow residue and the solid was broken up with a spatula. The solution was stirred until a fine white homogeneous precipitate was obtained. The solution was filtered and the solid washed with ether to yield 285 mg of 1-[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]-3-piperidinecarboxylic acid, ethyl ester (AIT-0103) as a white solid. Yield: 90%. m.p.: 171°-175°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:40]([CH3:41])=[CH:39][N:38]=[C:37]([CH3:42])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:22])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[C:40]([CH3:41])=[CH:39][N:38]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M123) (0.29 g, 0.46 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[OH-].[K+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([CH3:21])[N:15]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:17]=[C:16]([CH3:21])[N:15]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Methoxybenzyl alcohol (1.66 g, 12 mmol) was dissolved in DMF (20 mL). Potassium hydroxide (2.31 g, 36 mmol, 87%) was added and stirred at room temperature for 10 min followed by cooling to 0° C. 4,6-dichloro-2-methylpyrimidine (2.15 g, 13.2 mmol) was dissolved in DMF (4 mL) and added to the solution drop-wise. The internal temperature was controlled under 2° C. The reaction solution was kept at 0° C. for 2 h, then allowed to warm slowly to 16° C. over 1 hr. The reaction was diluted with ethyl acetate (50 mL), washed with brine (50 mL×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by chromatography on silica gel (eluting 7.7% ethyl acetate/hexane) to yield the titled compound as a colorless oil. LC-MS (M+1): 265.51, (M+23): 287.52.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
To a solution of 14.1 g (0.07 mole) of 4-chloro-3-nitrobenzoic acid in 200 ml of dry benzene, 10 ml of thionyl chloride is added and the mixture is refluxed for 10 hours. The excess of thionyl chloride is removed in vacuo and the acid chloride is purified by repeated addition of fresh benzene and subsequent removal in vacuo.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([OH:22])([C:16]1[N:17]([CH3:21])[CH:18]=[CH:19][N:20]=1)[CH2:12]2)=O)(C)(C)C.[ClH:23]>O1CCOCC1>[ClH:23].[CH3:21][N:17]1[CH:18]=[CH:19][N:20]=[C:16]1[C:11]1([OH:22])[CH2:10][CH:9]2[NH:8][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: Cn1ccnc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccnc1C1(O)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-Hydroxy-3-(1-methyl-1H-imidazol-2-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.12 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum. The solid was triturated from ether to afford the title compound (0.09 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH2:9])=[CH:4][C:3]=1[OH:10].[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]2[CH2:17][CH2:18][CH2:19][CH2:20][CH:12]12>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:10])=[CH:4][C:5]([N:9]2[C:14](=[O:15])[C:13]3[CH2:17][CH2:18][CH2:19][CH2:20][C:12]=3[C:11]2=[O:16])=[C:6]([F:8])[CH:7]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1cc(O)c(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Temperature: 25 °C
Yield: 34.8 %

Procedure:
2-Chloro-4-fluoro-5-aminophenol (6.6 g) and 2,4,5,6-tetrahydrophthalic anhydride (6 g) are dissolved in acetic acid (20 ml) and refluxed for 2 hours. The resultant mixture is allowed to cool to room temperature and poured into ice-water, followed by extraction with ether. The ether extract is washed with a saturated sodium hydrogen carbonate solution and water in order, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by silica gel-chromatography to give 4.0 g of N-(4-chloro-2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide. M.P., 151° C.