Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]([C:14]([O:16]C)=[O:15])[CH2:4][CH2:3]1.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([C:14]([OH:16])=[O:15])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
Methyl 5-oxo-1-(phenylmethyl)-prolinate (0.212 g, 0.91 mmol) was dissolved in water (3 ml) and methanol (0.5 ml) and treated with 2M aqueous sodium hydroxide (0.682 ml, 1.36 mmol). The mixture was stirred overnight at room temperature and then washed with dichloromethane. The aqueous layer was evaporated and the residue treated with an excess of 1M hydrogen chloride in ether (˜5 ml). The mixture was evaporated once more and the residue was triturated with dichloromethane. The solid material was discarded and the combined dichloromethane fractions were evaporated to give 5-oxo-1-(phenylmethyl)-proline (0.182 g) as a yellow oil which was used without further purification.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19]>CC#N>[CH3:16][C@H:3]([CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15]
Reactant: CCCOC1CCNCC1
Reactant: C[C@H](CI)Cn1c(=O)ccc2ccccc21
Solvent: CC#N
Product: CCCOC1CCN(C[C@@H](C)Cn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 25.6 %

Procedure:
A 4 mL vial was charged with crude (S)-1-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g), 4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH3CN (2.5 mL). The mixture was shaken at 50° C. for 24 h and then purified by cation-exchange CC followed by flash CC (SiO2; EtOAc/MeOH 1:4) to give the title compound (0.051 g, 17%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@H:9]([OH:21])[CH2:10][N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[C:4](=[O:22])[CH:3]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][C@@H:9]([OH:21])[CH2:8][N:5]1[CH:6]=[CH:7][C:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][C:4]1=[O:22]
Reactant: Nc1ccccc1
Reactant: O=c1cc(Br)ccn1C[C@H](O)CN1CCc2ccccc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: O=c1cc(Nc2ccccc2)ccn1C[C@H](O)CN1CCc2ccccc2C1
Temperature: 140 °C
Yield: 8.7 %

Procedure:
To a solution of (R)-4-bromo-1-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)pyridin-2(1H)-one (200 mg, 0.551 mmol) in anhydrous toluene (5 mL) was added aniline (51 mg, 0.551 mmol), xantphos (20 mg), Pd2(dba)3 (20 mg) and t-BuOK (123 mg, 1.102 mmol). The mixture was heated under microwave conditions at 140° C. for 1 h, filtered and concentrated. The crude product was purified by preparative HPLC purification. (18 mg, yield 8.7%) MS (ESI+) e/z: 376.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.45-7.35 (m, 3H), 7.24-7.18 (m, 2H), 7.17-7.08 (m, 4H), 7.07-7.02 (m, 1H), 6.11 (dd, J=2.6, 7.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 4.33 (dd, J=3.3, 13.4 Hz, 1H), 4.27-4.15 (m, 1H), 3.73 (s, 2H), 3.63 (dd, J=8.0, 13.6 Hz, 1H), 2.96-2.89 (m, 2H), 2.88-2.82 (m, 2H), 2.66-2.58 (m, 2H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12](C(=O)C(C2C3C(=NC=CC=3)NC=2)=O)[C@H:11](C)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[CH:39]=[N:38][C:37]([O:40][CH3:41])=[C:36]2[C:32]=1[C:33]([C:42](=[O:46])[C:43]([O-:45])=O)=[CH:34][NH:35]2.[K+]>>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:43](=[O:45])[C:42]([C:33]2[C:32]3[C:36](=[C:37]([O:40][CH3:41])[N:38]=[CH:39][C:31]=3[O:30][CH3:29])[NH:35][CH:34]=2)=[O:46])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12

Procedure:
Compound 5ao, N-(benzoyl)-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]-piperazine was prepared by the same method used to prepare compound 5a but the starting material was Potassium (4,7-dimethoxy-6-azaindole-3-yl)-oxoacetate. The compound was purified by silica gel chromatography using EtOAc as the eluting solvent to give a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]12[CH2:12][CH:11]([C:13]([OH:15])=O)[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2.C1C=CC=CC=1>ClCCl>[C:5]12[CH2:12][CH:11]([C:13]([Cl:3])=[O:15])[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1Cc2ccccc21
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(Cl)C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.5 ml) was added to a solution of bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid [14381-41-0] (0.001 mol) in dichloromethane. The reaction mixture was refluxed for 1 hour. Then stirred overnight at room temperature. The solvents were co-evaporated 2 times with benzene to obtain bicyclo[4.2.0]octa-1,3,5-triene-7-carbonyl chloride [1473-47-8] which was dissolved in DIPE. The obtained solution was added dropwise to a cooled mixture (0° C.) of N-allyl-2-adamantanamine [24161-63-5] and sodium carbonate in DIPE. The reaction mixture was stirred for 30 minutes on ice and then for 2 hours at room temperature. The mixture was poured out into water and extracted with dichloromethane. The organic layer was filtered through Extrelut™ and the filtrate was evaporated. The residue was purified by flash column chromatography on TRIKONEX FlashTube™ (eluent: CH2Cl2/EtOAc 90/10). The product fractions were collected and the solvents were evaporated, yielding 0.13 g of intermediate 1.
Reaction SMILES: [CH:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=2)[C:7]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[N:6]1)([CH2:3][CH3:4])[CH3:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[CH:15]=[C:10]([C:8]2[C:7]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[N:6][N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH:9]=2)[CH:11]=[CH:12][N:13]=1
Reactant: CCC(C)n1cc(-c2cc[n+]([O-])cc2)c(-c2ccc(Cl)s2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(C)n1cc(-c2ccnc(Cl)c2)c(-c2ccc(Cl)s2)n1
Yield: 29 %

Procedure:
4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine-N-oxide (6.1 mmol) was stirred in 20 mL of phosphorous oxychloride at 120° C. for 5 h. The solvent was then evaporated and the residue was treated with methanol and evaporated again. The residue was purified by chromatography on silica gel (hepthane:ethyl acetate 5:1 to 3:1) to afford 623 mg of 2-Chloro-4-[1-sec-butyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (29% yield).
Reaction SMILES: C(OC([NH:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH2:16]C)=[O:14])=O)C.C[O-].[Na+]>>[NH2:6][C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCOC(=O)NC1=C(C(=O)OCC)CCCC1
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C1=C(N)CCCC1
Yield: 77.1 %

Procedure:
Using the method of Example 1 Part B, ethyl 2-[(ethoxycarbonyl)amino]-1-cyclohexene-1-carboxylate (158 g, 0.66 mole) was reacted with sodium methoxide to provide 79 g of methyl 2-amino-1-cyclohexene-1-carboxylate as a white solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.[CH:25]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])[CH3:26].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([S:34][CH:31]5[CH2:32][CH2:33][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29][CH2:30]5)[CH:24]=[CH:23][C:5]=43)[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC(C)N1CCC(S)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(SC4CCN(C(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 120 °C
Yield: 70.5 %

Procedure:
A mixture of 8-bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (150 mg, 0.386 mmol), 1-isopropylpiperidine-4-thiol (92 mg, 0.579 mmol), Pd2(dba)3 (18 mg, 5 mol %), XantPhos (23 mg, 10 mol %) and DIPEA (0.27 mL, 1.54 mmol) in dioxane (4 mL) was purged with nitrogen and then heated at 120° C. for 1 h using microwave irradiation. After cooling to RT, the crude mixture was diluted with DCM (75 mL) and purified by column chromatography (Si-PCC, gradient 0-6% 2N NH3/MeOH in DCM followed by C18, gradient 20-50% MeOH in 0.5% TFA/H2O). The product containing fractions were combined and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The basic fractions were concentrated under reduced pressure affording 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-(1-isopropylpiperidin-4-ylsulfanyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a colorless solid (127 mg, 70%). LCMS: RT 3.00 min [M+H]+ 467.1
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=[C:9]2[CH:8]=1)=[O:6])[CH3:3].C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH2:38]([C:40]1[C:48]2[C:47]([NH2:49])=[CH:46][CH:45]=[CH:44][C:43]=2[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[N:41]=1)[CH3:39]>CN1C(=O)CCC1>[CH2:38]([C:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][C:47]=2[NH:49][C:16]([C:13]2[N:10]3[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][C:9]3=[N:15][CH:14]=2)=[O:18])[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([CH3:57])[N:52]=2)[N:41]=1)[CH3:39]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(N)c12
Reactant: CCOC(=O)c1ccn2c(C(=O)O)cnc2c1
Agent: Cl
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To 7-(ethoxycarbonyl) imidazo[1,2-a]pyridine-3-carboxylic acid hydrochloride (501 mg, 1.85 mmol) in NMP (10 mL) was added triethylamine (468 mg, 4.63 mmol). The suspension turned into a clear solution. 2,4,6-trichlorobenzoyl chloride (474 mg, 1.94 mmol) was added dropwise to the reaction mixture. A milky suspension resulted after 10 minutes. The mixture was stirred for another 30 minutes. 3-Ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (444 mg, 1.67 mmol) was added in one portion to the reaction mixture. The mixture was sealed and heated to 75° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure to remove NMP. The residue was diluted with EtOAc/H2O (20 mL/10 mL). The organic phase was washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrated. Silica gel chromatography (EtOAc/Hexane 5:1 to 10:1) provided the final product (665 mg). MS (ES+APCI) m/z=483 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH2:23][NH:24][S:25]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH:22]=[C:17]2[CH:16]=[CH:15]1>>[Cl:8][C:7]1[C:2]([N:24]([CH2:23][C:21]2[CH:22]=[C:17]3[CH:16]=[CH:15][N:14]([CH3:13])[C:18]3=[N:19][CH:20]=2)[S:25]([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)(=[O:26])=[O:27])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3c(ccn3C)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 37).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[O:28]1[C:32]2([CH2:37][CH2:36][N:35]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1>>[O:31]1[C:32]2([CH2:33][CH2:34][N:35]([C:38]3[CH:45]=[CH:44][C:41]([C:42]4[NH:25][C:24]5[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]6[CH:14]=[CH:13][C:12]([N:15]7[CH2:20][CH2:19][O:18][CH2:17][CH2:16]7)=[CH:11][CH:10]=6)=[CH:5][C:4]=5[N:1]=4)=[CH:40][CH:39]=3)[CH2:36][CH2:37]2)[O:28][CH2:29][CH2:30]1
Reactant: O=Cc1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCC5(CC4)OCCO5)cc3)nc2c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 413 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 4-(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)benzaldehyde. [M+H]+ calcd for C31H33N5O4: 540.25; found: 540.05.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:13])=[CH:8][N:7]([CH:10]([F:12])[F:11])[N:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccn(C(F)F)n1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(F)F)cc1Cl
Temperature: 50 °C
Yield: 85.5 %

Procedure:
A mixture of 1-difluoromethyl-1H-pyrazole-3-carboxylic acid methyl ester (535 mg, 3 mmole) and N-chloro-succinimide (1.22 g, 9.1 mmole) in DMF (5 ml) was heated at 50° C. overnight. The reaction mixture was cooled, partitioned between AcOEt and water, the organic layer was washed with water, dried, evaporated and the residue was purified by chromatography on silica gel using cyclohexane/AcOEt (3:1) to give the title compound (540 mg) as a white solid. MS: m/z=209.9 [M]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]([C:33]4[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=4)[C:36]([O:38][CH2:39][C:40]4[O:41][C:42](=[O:46])[O:43][C:44]=4[CH3:45])=[O:37])[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)[N:10]=[N:9]2)C=CC=CC=1.C(O)(=O)C.O>O1CCOCC1>[CH3:45][C:44]1[O:43][C:42](=[O:46])[O:41][C:40]=1[CH2:39][O:38][C:36](=[O:37])[C:35]1[CH:47]=[CH:48][CH:49]=[C:33]([N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:11]3[NH:10][N:9]=[N:8][N:12]=3)=[CH:20][CH:21]=2)[C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:34]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1)c1cccc(C(=O)OCc2oc(=O)oc2C)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1cccc(C(=O)OCc2oc(=O)oc2C)c1
Temperature: 40 °C
Reaction time: 7 h
Yield: 61.8 %

Procedure:
To a solution of the obtained (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 3-[N-[[4-[2-(3-triphenylmethyl-3H-tetrazol-5-yl)phenyl]phenyl]methyl]-N-pentanoylamino]benzoate (11.57 g) in dioxane (80 ml) were added acetic acid (60 ml) and water (20 ml), and the mixture was stirred at 40° C. for 7 hrs. The reaction mixture was concentrated to give a solid, and the residue was purified by silica gel column chromatography (methylene chloride-methanol:10-1 v/v) to give the object compound (5.01 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]([CH:10]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH3:9])=[O:7].C(N(CC)CC)C.[Cl:43][C:44]1[CH:50]=[C:49]([CH3:51])[CH:48]=[CH:47][C:45]=1[NH2:46]>C(Cl)Cl.C(OCC)(=O)C>[Cl:43][C:44]1[CH:50]=[C:49]([CH3:51])[CH:48]=[CH:47][C:45]=1[NH:46][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH:10]([N:8]([C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=1)[CH3:9])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCCC(=O)O)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(N)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)CCCC(Cc2c[nH]c3ccccc23)N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
160 mg (0.268 mmol) of 5-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-6-(1H-indol-3-yl)-hexanoic acid are dissolved in 10 ml of methylene chloride, and then 222 ml (1.34 mmol) of triethylamine, 48 ml (0.382 mmol) of 2-chloro-4-methyl-aniline and 271 ml of 50% propylphosphonic acid anhydride solution in ethyl acetate are added. The reaction mixture is stirred at room temperature for 20 hours, then washed twice with aqueous potassium carbonate solution. The aqueous phase is extracted twice with methylene chloride, and the organic phases are combined, dried over magnesium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/petroleum ether (first 1:2, then 3:1). The title compound is obtained in the form of white crystals. MS (EI): 352, 241, 222, 213, 130. TLC: ethyl acetate, Rf =0.59.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C:13]2=[N:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC[C@@H]1OC[C@]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])NOC[C@@H]2C1)C1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:19][CH2:18][C@:13]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=3[F:45])[NH:14][O:15][C@@H:16]([CH3:17])[C@@H:12]2[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc([C@]23CO[C@@H](COCc4ccccc4)C[C@H]2CON3)c(F)c1
Reactant: C[C@@H]1ON=C2CO[C@@H](COCc3ccccc3)C[C@H]21
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@@H]12

Procedure:
The product, obtained as a yellow oil, was prepared from (3S,3aR,5R)-5-[(benzyloxy)methyl]-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C13) according to the general procedure for the synthesis of (3aR,5R,7aS)-5-[(benzyloxy)methyl]-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C5) in Preparation P1. Yield: 21.5 g, 57.2 mmol, 48%. LCMS m/z 376.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.98 (ddd, J=9.1, 9.1, 6.8 Hz, 1H), 7.28-7.40 (m, 5H), 6.87-6.93 (m, 1H), 6.80 (ddd, J=11.9, 8.6, 2.6 Hz, 1H), 4.60 (AB quartet, JAB=12.1 Hz, ΔνAB=19.9 Hz, 2H), 3.99-4.06 (m, 1H), 3.97 (dd, half of ABX pattern, J=12.9, 2.0 Hz, 1H), 3.80-3.88 (m, 2H), 3.56 (dd, half of ABX pattern, J=10.2, 6.3 Hz, 1H), 3.49 (dd, half of ABX pattern, J=10.2, 4.1 Hz, 1H), 2.81-2.87 (m, 1H), 2.04 (ddd, J=14.2, 7.6, 2.8 Hz, 1H), 1.48-1.59 (m, 1H), 0.79 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].ClC1C=CC=CC=1C1C(C2C=CC(Cl)=CC=2)=CC2N(C(=O)NN=2)N=1>>[Cl:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:4][C:5]2[N:6]([C:17](=[O:18])[NH:9][N:8]=2)[N:7]=1
Reactant: NNc1cc(-c2ccc(Cl)cc2)c(Cl)nn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Product: O=c1[nH]nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Yield: 80 %

Procedure:
The title compound (900 mg, 80%) as a yellow solid was prepared from 1-(6-chloro-5-(4-chlorophenyl)pyridazin-3-yl)hydrazine (1.02 g, 4.0 mmol) and 1,1′-carbonyl diimidazole (3.24 g, 20.0 mmol) according to the procedures described for 6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 1G). LC/MS (method A): retention time=2.77 min, (M+H)+=281.
Reaction SMILES: C([O-])(=O)C.[Na+].ClC(Cl)C(O)=O.Cl.[NH2:13][OH:14].O[C:16]1([CH3:35])[C:22]2[CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:21]=2[CH:20]=[CH:19][C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]1=2>ClCCl>[OH:14][NH:13][C:16]1([CH3:35])[C:22]2[CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[C:21]=2[CH:20]=[CH:19][C:18]2[CH:31]=[CH:32][CH:33]=[CH:34][C:17]1=2
Reactant: CC1(O)c2ccccc2C=Cc2c1ccc1ccccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: CC1(NO)c2ccccc2C=Cc2c1ccc1ccccc21
Temperature: 0 °C

Procedure:
Sodium acetate (5.7 g) and dichloroacetic acid (8.5 ml) were stirred together in dichloromethane (8.5 ml) at 0° C. for 5 minutes then hydroxylamine hydrochloride (4.8 g) added. After 1 h at room temperature more dichloromethane (17 ml) was added and after a further 30 minutes, the product from Example 7. Step A (1.9q) was added. After 1 h at room temperature the reaction mixture was poured into ice-water (200 ml) and washed with ammonia solution (70 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the required product (2.04 g) as a colourless form. Spectral data were consistent with the proposed structure.
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8])[CH2:4][CH3:5]>O1CCCC1.CO>[CH2:3]([N:6]([C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:8])[CH2:4][CH3:5]
Reactant: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(CCC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 85 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 6.4 eq) of sodium hydroxide and 680 mg (1.55 mmol, 1 eq) of methyl (E)-3-[3′-(1-propyl-3-heptylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 560 mg of (E)-3-[3′-(1-propyl-3-heptylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=126° C.). Yield=85%
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]3[C:16]([NH:17][CH:19]([CH3:21])[CH3:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1cccnc1Nc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Nc1cccnc1Nc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
The N2-(benzo[d][1,3]dioxol-5-yl)pyridine-2,3-diamine (8.5 g, 37.1 mmol) was dissolved in dichloromethane (150 mL). Acetone (4.1 mL, 55.6 mmol), sodium triacetoxyborohydride (11.79 g, 55.6 mmol) and acetic acid (4.2 mL, 74.2 mmol) were added to it. This was stirred at ambient temperature for 18 h. The mixture was washed with 1N NaOH and then washed with water. The organic layer was concentrated in vacuo and chromatographed using a gradient of 0-10% ethyl acetate in dichloromethane to give N2-(benzo[d][1,3]dioxol-5-yl)-N3-isopropylpyridine-2,3-diamine (7.8 grams, 78%).