Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28](OC)=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:4].[CH2:5]([O:12][C:13]([NH:15][C@H:16]([C:24]([N:26]1[CH2:34][CH2:33][CH2:32][C@H:27]1[C:28]([N-:3][CH2:1][CH3:2])=[O:29])=[O:25])[CH2:17][CH2:18][CH2:19][NH:20][C:21](=[NH:23])[NH2:22])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Reactant: CCN
Agent: Cl
Solvent: CO
Product: CC[N-]C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1

Procedure:
Nα -Benzyloxycarbonyl-L-arginyl-L-prolyl-N-ethylamide, hydrochloride is prepared according to the following method. To a cold solution of 9.7 g. ethylamine in 50 ml. of methanol is added 2 g. of Nα -benzyloxycarbonyl-L-arginyl-L-proline, methyl ester, hydrochloride. The reaction is let stand in a sealed pressure bottle at room temperature and then warmed occasionally to 40°-45° C. during 8 days. It is then evaporated to small volume under reduced pressure. The residual solution is dropped into stirred ethyl ether to precipitate a somewhat sticky white solid which is dried under reduced pressure; [α]D25 -53° (c. 1.02, methanol).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C.O>[CH3:25][O:24][CH2:23][CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reaction time: 1 h
Yield: 116.1 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 1-bromo-2-methoxyethane (0.41 mL, 4.3 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. After the initial heating, additional 1-bromo-2-methoxyethane (0.41 mL) was added to the reaction. Heating was repeated for an additional 1 hr. The crude reaction mixtures were then diluted with water (250 mL) and extracted with ethyl acetate (3×50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to give 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g) as a light yellow oil. ESI-MS:m/z 253.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([C:63]([O:65][CH2:66][C:67]([C:70]([OH:72])=O)([CH3:69])[CH3:68])=[O:64])[CH:60]2[CH2:62][CH2:61]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN.C(N(CC)CC)C>CC#N>[C:25]([O:29][C:30]([N:32]1[CH2:36][C@@H:35]([CH2:37][N:38]([CH:55]([CH3:57])[CH3:56])[C:39](=[O:54])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:41]=2)[C@H:34]([CH2:58][N:59]([CH:60]2[CH2:61][CH2:62]2)[C:63]([O:65][CH2:66][C:67]([CH3:69])([C:70](=[O:72])[NH:2][CH3:1])[CH3:68])=[O:64])[CH2:33]1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)O)C2CC2)C(C)C)ccc1OC
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)C(C)(C)COC(=O)N(C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C)C1CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
HBTU (161 mg, 0.43 mmol) is added to a solution of (3S*,4R*)-3-{[(2-carboxy-2-methyl-propoxycarbonyl)-cyclopropyl-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (240 mg, 0.35 mmol) in CH3CN (10 mL) at 0° C. After 5 min a solution of methylamine (44 μL, 0.35 mmol, 8M in EtOH) and triethylamine (493 μL, 3.54 mmol) in CH3CN (10 mL) is added at 0° C. and the reaction solution is stirred at RT for 5 h. Another portion of methylamine (0.22 mL, 1.75 mmol) is added and stirring is continued for another 16 h. Then, triethylamine (247 μL, 1.77 mmol) and HBTU (268 mg, 1.02 mmol) are added and the reaction mixture is stirred at 50° C. for another 16 h. The solvent is evaporated and the crude product purified by HPLC (Interchrom C18 ODB 10 μm, 28×250 mm, eluent: CH3CN/H2O 5%/2.5 min, CH3CN/H2O 5-100%/23 min, 100% CH3CN/4.5 min, flow 40 mL/min) to give the title compound. MS (LC-MS): 691.4 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.38 min.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([O:23][CH3:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CN(C=O)C>>[CH3:24][O:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: COC1(c2ccc(Br)cc2)CCC1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COC1(c2ccc(C=O)cc2)CCC1
Yield: 69 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methoxycyclobutyl)-benzene (140 mg, 0.58 mmol), n-BuLi (363 μl, 1.6M solution in hexane, 0.58 mmol) and DMF (90 μl, 1.16 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methoxycyclobutyl)-benzaldehyde (76 mg, 69%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 10.03 (s, 1H), 7.91 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 2.96 (s, 3H), 2.45-2.39 (m, 4H), 1.99 (m, 1H), 1.73 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=N[CH:13]=2)=[CH:4][CH:3]=1.F[C:33]1C=CC(C2C=CC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=O)CC3)=NC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:33][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Yield: 61 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.072 g), to give the title compound as a white solid (0.047 g, 61%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:14]2[CH2:19][CH2:18][N:17](C(=O)C)[CH2:16][CH2:15]2)[O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:25]([OH:27])[CH3:26]>O>[CH2:25]([O:27][CH2:2][C:3]1[N:4]=[C:5]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[O:6][C:7]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:26]
Reactant: CC(=O)N1CCC(c2nc(CCl)c(-c3ccccc3)o2)CC1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(C2CCNCC2)oc1-c1ccccc1

Procedure:
A solution of 1-[4-(4 -chloromethyl-5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethanone (0.200 g, 0.627 mmol), prepared as in intermediate 3B, in ethanol (4.5 ml) is treated with a solution of NaOH (0.501 g, 12.55 mmol) in water (1/.5 ml). The reaction mixture is heated to 75 C for 48 hours, concentrated, and the residue partitioned between EtOAc and water. The aqueous phase is washed with EtOAc (twice). The organic phases are combined and washed with saturated brine, dried (Na2SO4) and concentrated to afford the title compound as a light orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Yield: 70.3 %

Procedure:
0.846 g (3 mmol) of the product obtained in step d) were dissolved in 100 ml of dry ethanol. 150 mg of 10% palladium on charcoal were added, and the suspension was hydrogenated at 50° C. and 4 bar hydrogen pressure. After filtration the solvent was removed in vacuo. 0.6 g of a colourless oil were obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[OH:16])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[O:16]1[C:4]2[CH:5]=[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:14]=[CH:15][C:3]=2[CH:1]=[C:24]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC(C)(C)C)cc2o1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of tert-butyl 4-formyl-3-hydroxybenzoate (1.2 g, 5.40 mmol) and potassium carbonate (1726 mg, 12.4 mmol) in DMF (17 ml) was admixed dropwise with ethyl bromoacetate (0.56 ml, 5.0 mmol) and stirred at 80° C., for 6 h. Then ethyl bromoacetate (0.28 ml, 2.5 mmol) was added again and the mixture was stirred at 80° C. overnight. After cooling to room temperature, the reaction mixture was added to ice-water and extracted with ethyl acetate. The organic phases were dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].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.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:9]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:13][CH:12]=1)=[O:11])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 4-tert-butylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.30 (s, 9 H) 1.32-1.38 (m, 2 H) 1.71-1.78 (m, 2 H) 2.48 (s, 3 H) 4.21 (t, 2 H) 6.67 (s, 1 H) 7.47 (d, 2 H) 7.91 (d, 2 H); MS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][C@H:11]([CH3:30])[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:31]=[C:8]([CH:9]=[N:10][CH:11]([CH3:30])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[OH:13])[C:7]([OH:32])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](C)N=Cc1cc([N+](=O)[O-])ccc1O
Solvent: Cc1ccccc1
Product: COc1ccccc1C(O)(c1ccccc1OC)C(C)N=Cc1cc([N+](=O)[O-])ccc1O
Temperature: 10 °C
Yield: 82 %

Procedure:
19.6 g (44.9 mmol) of (R)-N-(5-nitrosalicylidene)-2-amino-1,1-di(2-methoxyphenyl)-1-propanol, 8.96 g (44.9 mmol) of cupric acetate, and 160 g of toluene were mixed in a flask and reacted at 80° C. for 1 hr under stirring. The reaction solution was cooled to 10° C. and blue-green chrystalls were deposited. Deposited crystals were collected by filtration, washed with 50 g of cold toluene, and dried at room temperature to give 19.1 g of a copper complex of (R) N-(5-nitrosalicylidene)-2-amino-1,1-di(2-methoxyphenyl)-1-propanol in a yield of 82.0%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[H-].[Na+].[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32]Br)(=[O:23])[CH3:22].C(O)(=O)C>CN(C=O)C>[C:21]([O:24][CH2:25][C@@H:26]1[CH2:31][CH:30]=[CH:29][CH2:28][C@@H:27]1[CH2:32][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1CBr
Reactant: Nc1nc(OCc2ccccc2)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1Cn1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-amino-6-benzyloxypurine (1 mmol) in DMF (2 mL) was added sodium hydride (1.15 eq) and the mixture stirred at room temperature for 30 minutes. A solution of 1(R)-acetoxymethyl-2(S)-bromomethylcyclohex-4-ene (1.1 eq) in DMF (0.75 mL) and the reaction stirred at 60° C. for 16 hours. The reaction was neutralized with acetic acid and concentrated. The desired compound was purified by silica gel chromatography (chloroform:methanol 95:5) as a colorless foam. 1HNMR (500 mHz, CDCl3): 8.02 ppm (s, 1H); 7.65 (s, 1H); 7.49 (d, 2H); 7.38-7.26 (m, 3H); 5.65 (dd, 2H); 5.56 (s, 2H); 4.33 (dd, 1H); 4.12 (dd, 1H); 4.06-3.97 (m, 2H); 2.40 (bs, 1H); 2.23-1.75 (m, 6H); 2.20 (s, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][NH:16][CH2:17]2)[CH2:13][CH2:12]1)=[O:9].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O.C(O)(=O)C.C([BH3-])#N>ClCCl>[O:23]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]([CH2:19][CH:20]([CH3:21])[CH3:22])[C:8]([NH:10][C@H:11]1[C@H:18]2[C@H:14]([CH2:15][N:16]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([C:25]([F:24])([F:34])[F:35])[CH:27]=3)[CH2:17]2)[CH2:13][CH2:12]1)=[O:9]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CNC[C@H]21)N1CCCS1(=O)=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)N1CCCS1(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2S)-2-(1,1-Dioxidoisothiazolidin-2-yl)-4-methyl-N-[(3aS,4R,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]pentanamide (204 mg, 0.594 mmol) and 3-(trifluoromethyl)benzaldehyde (0.158 mL, 1.188 mmol) were dissolved in dichloromethane (3 mL). Acetic acid (1 mL) was added. The reaction was stirred at ambient temperature for 20 min, then PS-cyanoborohydride (487 mg, 1.188 mmol) was added. The reaction was stirred at room temperature overnight, then filtered, and the solvent was removed in vacuo. The crude material was purified by silica gel chromatography using 1-10% methanol (2 N ammonia)/dichloromethane to the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.79 (d, J=7.0, 1H), 7.75 (d, J=10.3, 1H), 7.61-7.54 (m, 2H), 7.44 (t, J=7.7, 1H), 4.52 (dd, J=6.6, 8.9, 1H), 4.38 (dq, J=6.4, 12.6, 1H), 3.94 (dd, J=7.3, 16.2, 1H), 3.57 (dd, J=9.1, 13.5, 1H), 3.50-3.37 (m, 2H), 3.31-3.19 (m, 2H), 2.79 (ddd, J=3.0, 9.1, 19.0, 1H), 2.62-2.54 (m, 1H), 2.54-2.45 (m, 1H), 2.43-2.36 (m, 1H), 2.31-2.16 (m, 4H), 2.13-2.03 (m, 1H), 1.94-1.78 (m, 3H), 1.77-1.59 (m, 2H), 1.39 (dt, J=6.5, 19.8, 1H), 0.88 (d, J=6.6, 3H), 0.82 (dd, J=2.3, 6.5, 3H); MS (ESI+) m/z 502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]([S:13]([CH3:15])=O)[C:5]2=[O:16].[C:17]([O:20]C(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:20][CH2:15][S:13][C:6]1[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]([CH3:12])[N:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1nc(S(C)=O)c(=O)c2cc(Cl)ccc21
Product: CC(=O)OCSc1nn(C)c2ccc(Cl)cc2c1=O
Reaction time: 8 h

Procedure:
A mixture of 8 g of 6-chloro-1-methyl-3-(methylsulfinyl)-4(1H) cinnolinone and 30 ml of acetic anhydride was refluxed for 21/2 hrs. The resulting solution was allowed to stand at room temperature overnight. The crystalline precipitate was filtered off, washed with Skelly B, and recrystallized from CH3CN, mp. 191°-92°; yield 6 g (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:16][C:17](O)([CH3:19])[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17]([O:14][C:13]([C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9][S:10][CH:11]=1)=[O:15])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)O
Reactant: O=C(O)c1csnc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1csnc1-c1ccc(Cl)cc1

Procedure:
To a mixture of 7 (3.35 g), DMAP (1.7 g) and tBuOH (5.2 g) in CH2Cl2 (50 ml) is added 3.2 g of EDCI and the clear solution is stirred over the weekend. Additional CH2Cl2 (100 ml) is added and the mixture is washed with 1N HCl (2×150 ml), sat. NaHCO3 (150 ml), brine (150 ml), dried and concentrated. This afforded 3.75 g of 8 as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[SH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(O)C.O>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[CH2:2][S:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: Sc1ncccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1cnc(SCc2nc3ccccc3[nH]2)nc1

Procedure:
10.0 g (0.06 mole) of 2-chloromethylbenzimidazole are added to a solution of 6.7 g (0.06 mole) of 2-mercaptopyrimidine and 2.4 g (0.06 mole) of sodium hydroxide in 200 ml of ethanol and 20 ml of water. The mixture is maintained under reflux for 2 hours and the ethanol evaporated off. The residue is taken up with water (50 ml) and extracted with ethyl acetate (3×50 ml), the organic phase is dried with sodium sulfate, filtered and evaporated to a volume of 40 ml of solution, in which there crystallize 10.2 g (70%) of 2-(2-benzimidazolylmethylthio)pyrimidine, melting point 154°-155° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:22]=[C:23](N)[C:6]=2[N:5]=1)[CH3:3].[OH:31]S(O)(=O)=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[CH3:3][CH:2]([C:4]1[N:8]([CH2:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[C:7]2[CH:20]=[C:21]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:22]=[C:23]([OH:31])[C:6]=2[N:5]=1)[CH3:1]
Reactant: CC(C)c1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a solution of 2-(1-methylethyl)-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazol-4-amine (300 mg) in H2O (20 mL), and conc. H2SO4 (1 mL) was added aqueous NaNO2 (78 mg) solution dropwise at 0° C. The mixture was stirred at 0° C. for 15 min and then heated to reflux for 1 h. The mixture was cooled to room temperature and the pH neutralized with aqueous NaHCO3 solution. The solution was extracted with DCM (250 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with EtOAc:petroleum ether=1:1 to afford the desired product as a solid (80 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (d, 6H, J=6.6 Hz), 2.91 (t, 4H, J=7.5 Hz), 3.03 (m, 1H, J=6.6 Hz), 3.64 (t, 4H, J=7.5 Hz), 5.89 (s, 2H), 6.27-6.34 (m, 3H), 7.32 (t, 1H, J=7.5 Hz), 7.59-7.70 (m, 2H), 7.83 (d, 1H, J=7.5 Hz), 8.00 (d, 1H, J=7.5 Hz), 8.27 (d, 1H, J=7.5 Hz), 9.55 (s, 1H); LC-MS: m/e=402 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:33][O:24][C:23]([C:18]2([C:20]([O:22][CH2:33][CH:30]3[CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:32][CH2:31]1
Reactant: OCC1CC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CC1)(C(=O)OCC1CC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopropylmethanol according to the procedure of Example 30 as a white solid (HCl salt); 1H NMR (CDCl3) δ 0.33 (m, 4H), 0.61 (m, 4H), 1.21, (m, 2H), 1.32 (bs, 3H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.15 (d, J=7.3 Hz, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1 H); IR (KBr): 1757, 1778 cm-1 (C=O); MS (ES) m/z 530 (MH+); [α]D25 -26° (c, 1.0, CHCl3). Anal. Calcd. for C28H32ClNO7 ·HCl: C, 59.37; H, 5.69; N, 2.47; Cl, 12.53. Found: C, 59.19; H, 5.88; N, 2.29; Cl, 12.87.
Reaction SMILES: CN(C=O)C.[CH2:6]([Cl:8])Cl.C(Cl)(=O)C(Cl)=O.[N:15]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2C(=O)[NH:17][CH:16]=1>O>[Cl:8][C:6]1[C:19]2[CH:23]=[CH:22][S:21][C:20]=2[N:15]=[CH:16][N:17]=1
Reactant: O=c1[nH]cnc2sccc12
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2sccc12
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of DMF (90 μL) and CH2Cl2 (2 mL) at 0° C. under N2, oxalyl chloride (148 mg, 1.2 mmol) is added slowly and stirred for 10 min. 3H-Thieno[2,3-d]pyrimid-4-one (81 mg, 0.52 mmol) is added as a solid to the solution and warmed with a heat gun until the solid dissolves. The reaction is stirred at 25° C. for 12 h under N2. The reaction mixture is poured into water and extracted with CH2Cl2 . The phases are separated and the organic layer is dried (Na2SO4) and stripped under reduced pressure to yield 4-chlorothieno[2,3-d]pyrimidine (87.6 mg, 97%) as a solid. 1H NMR (DMSO) δ 8.96 (1H, s), 8.17 (1H, d, J=6.0 Hz), 7.62 (1H, d, J=6.0 Hz).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:21]=1[NH2:22]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:22][C:21]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:20]=3[F:19])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cc(F)c(F)cc1F
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)cc1F
Yield: 62.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2,4,5-trifluoroaniline in place of the 2,4-difluoroaniline. 230 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(2,4,5-trifluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following: