Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])=[C:16]([CH2:19][P+](C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]=O.P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[C:2]1([CH2:8][C:9]([NH:11][C@@H:12]2[C:47](=[O:48])[N:14]3[C:15]([C:39]([O:41][CH2:42][C:43]([Cl:44])([Cl:46])[Cl:45])=[O:40])=[C:16]([CH:19]=[CH2:49])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=P([O-])([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1

Procedure:
[7β-Phenylacetamido-4-(2,2,2-trichloroethoxycarbonyl) ceph-3-em-3-ylmethyl]-triphenylphosphonium bromide (403 mg, 0.5 mmole) was dissolved in N,N-dimethylformamide (10 ml.) and 40%-formaldehyde solution (3 ml.) was added. The solution was stirred vigorously while a solution of disodium hydrogen phosphate (400 mg.) in water (5 ml.) was added dropwise. A white crystalline solid, subsequently identified as the title ester, separated before the addition was complete. The reaction mixture was diluted with chloroform (5 ml.) and water (10 ml.), whereupon the solid dissolved. The aqueous phase was re-extracted with chloroform (25 ml.), and the combined organic phases were washed with 2N-hydrochloric acid (50 ml.) and water (4 × 25 ml.), dried (MgSO4), and evaporated to give the title ester as a pale-yellow solid (128 mg., 54%), λmax. (EtOH) 297 nm (ε13,700). Crystallisation by trituration with ethanol (2 ml.) gave a white solid (75 mg., 31.5%), m.p. 163 to 165°, [α]D23 - 54° (C 1.15; Me2SO), λmax. (EtOH) 297 nm (ε 13,550), νmax. (CHBr3) 3410 (NH), 1772 (azetidin- 2-one), 1730 (CO2R), 1674 and 1500 (CONH) and 912 cm-1 (=CH2), τ (CDCl3) 2.68 (5H, s; C6H5), 2.84 (1H, dd, J 11 and 18 Hz; CH=CH2), 3.61 (1H, d, J 8 Hz; NH), 4.13 (1H, dd, J 8 and 5 Hz; C7 -H), 4.48 (1H, d, J 18 Hz) and 4.60 (1H, d, J 11 Hz) (CH=CH2), 4.98 (1H, d, J 5 Hz; C6 -H), 4.99 and 5.25 (2H, AB-q, J 12 Hz; CH2CCl3), 6.30 and 6.53 (2H, AB-q J 18 Hz; C2 -H2), 6.37 (2H, s; C6H5CH2) (Found: C, 46.8, 47.1; H, 3.6, 3.6; Cl, 21.8; N, 5.5, 5.5; S, 6.5. C19H17Cl3N2O4S (475.8) requires C, 48.0; H, 3.6; Cl, 22.4; N, 5.9; S, 6.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]2)=[CH:25][CH:24]=1)=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-bromo-4-methoxy-benzoic acid (500 mg), 4-(4-methyl-piperazin-1-yl)-phenylamine (413 mg), EDAC (828 mg), HOBT (534 mg) and N-methylmorpholine (712 μl) in DMF (3 ml) was stirred at room temperature for 18 h. The mixture was then diluted with water (30 ml) and the resulting solid collected by filtration and dried (840 mg)
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:11])[CH:10]=1>CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:11])[CH:10]=1
Reactant: C[O-]
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 8.80 ml, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water (3×300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O.C(#N)C>O>[NH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1
Reactant: CC(C)(C)OC(=O)NCCn1cnc2c(N)nc3ccccc3c21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCn1cnc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Tert-butyl N-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate (14.8 g, 45.2 mmol), trifluoroacetic acid (100 mL) and acetonitrile (100 mL) were combined and maintained at ambient temperature overnight. The acetonitrile was removed and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated under vacuum to provide a tan solid. This material was dissolved in a minimal amount of hot water. The solution was adjusted to pH 14 and allowed to cool. The solution was concentrated under vacuum. The resulting residue was extracted with refluxing ethanol. The ethanol extract was concentrated under vacuum to provide 3.0 g of 1-(2-aminoethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a tan solid, m.p. 265° C. 1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 8.08 (dd, J=8.0, 1.5 Hz, 1H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (dt, J=8.0, 1.5 Hz, 1H), 7.25 (dt, J=8.0, 1.5 Hz, 1H), 6.58 (broad s, 2H), 4.54 (t, J=7.0 Hz, 2H), 3.01 (t, J=7.0 Hz, 2H), 1.60 (broad s, 2H); MS (EI) m/e 227.1171(227.1171 calcd for C12H13N5).
Reaction SMILES: [O:1]1[CH:6]([C:7]([O-:9])=[O:8])[CH:2]1[C:3]([O-:5])=[O:4].[Ca+2:10].[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>O>[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[Ca+2:10].[O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C([O-])C1OC1C(=O)[O-]
Reactant: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: O
Product: O=C(O)C1OC1C(=O)O
Product: O=S(=O)([O-])[O-]

Procedure:
One attempt to decrease the objectionable impurities obtained by the hydrolysis of epoxysuccinate to d,1-tartaric acid is described in U.S. Pat. No. 4,028,407 to Petritsch. In the approach toward purity of product taken by this patentee, tartaric acid was obtained by first epoxidizing calcium acid maleate in the usual manner with a tungsten acid-containing catalyst and reacting the resulting calcium acid epoxysuccinate with sulfuric acid to form a calcium sulfate and epoxysuccinic acid. An organic solvent is employed either alone or with water as a medium in which to react the calcium epoxysuccinate with sulfuric acid to obtain calcium sulfate and epoxysuccinic acid. The epoxysuccinic acid is hydrolyzed in the usual manner by boiling an aqueous solution at low pH to provide the desired tartaric acid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:7][N:8]2[C:17]([CH:18]=1)=[C:16]1[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]1)=[N:10][C:9]2=[O:19])(=O)C.[OH-].[Na+].Cl.O>CO>[OH:4][CH2:5][C:6]1[NH:7][N:8]2[C:17]([CH:18]=1)=[C:16]1[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]1)=[N:10][C:9]2=[O:19]
Reactant: CC(=O)OCc1cc2c3ccccc3nc(=O)n2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1nc2ccccc2c2cc(CO)[nH]n12
Reaction time: 5 h

Procedure:
The crude acetate product from Example 5 is slurried in a solution of 0.3 g of sodium hydroxide in 10 ml of aqueous methanol (1:1). After stirring for 5 hours, the reaction mixture is neutralized with concentrated hydrochloric acid followed by the addition of 13 ml of distilled water. After stirring overnight, the product is filtered, washed with cold distilled water and dried under vacuum at 60° C. to 0.62 g (72%) of white product, m.p. 285.0°-288.0° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[N:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.[Li+].[OH-]>C1COCC1.O.CO.CO.Cl>[C:26]1([C:22]2[CH:21]=[C:20]([C:17]3[N:14]4[N:15]=[CH:16][C:11]([C:7]5[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=5)[C:4]([OH:32])=[O:3])=[CH:12][C:13]4=[N:19][CH:18]=3)[CH:25]=[CH:24][N:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnn3c(-c4ccnc(-c5ccccc5)c4)cnc3c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid ethyl ester (1 eq, 0.119 mmol, 50 mg) (Ex. 42) is dissolved in THF/H2O/MeOH (0.5/0.25/0.25 ml) and LiOH (20 eq, 2.38 mmol, 57 mg) is then added and the reaction is stirred at room temperature for 1 h. The reaction mixture is then diluted with MeOH and HCl (1M) is added. The precipitate is filtered and dried to afford 3-[3-(2-Phenyl-pyridin-4-yl)-imidazo[1,2-b]pyridazin-7-yl]-benzoic acid as a yellow solid which did not require further purification; [M+H]+=393
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[S:23][CH:24]=1)([CH3:19])[CH3:18])[CH3:14].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:53])(=O)=O)=CC=1.[NH4+].[Cl-]>C1COCC1>[CH2:13]([O:15][C:16](=[O:42])[C:17]([C:20]1[N:21]=[C:22]([N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[S:23][C:24]=1[F:53])([CH3:19])[CH3:18])[CH3:14]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C(C)(C)c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1nc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)sc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
Under anhydrous condition n-BuLi (3.6 M solution in hexane, 2.55 mL, 9.20 mmol) was added to stirred solution of N,N-Diisopropyl amine (1.29 mL, 9.20 mmol) in 10 mL dry THF at −78° C. and reaction mixture was stirred for 1 hr. A solution of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (synthesized as per preparation 44; 2.0 g, 4.60 mmol) in 10 mL of dry THF was added dropwise to above reaction mixture and continued to stir for an additional 1 hr at −78° C. N-Fluorobenzenesulfonimide (2.17 g, 6.90 mmol) dissolved in 10 mL dry THF was added to reaction mixture dropwise and resulted reaction mixture was allowed to warm 0° C. within 3 hrs. Reaction mixture was poured on aq. saturated solution of NH4Cl (50 mL), mixture was then extracted with (3×50 mL) ethyl acetate; organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and washed with ethyl acetate and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (4% ethyl acetate in hexane) to afford pure compound (0.5 g).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:18][CH3:19])=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:10]=2)[CH:6]=[C:5]1[C:39]([OH:41])=[O:40])([CH3:3])[CH3:2].I[CH:43]([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1COCC1.O>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[C:13]3[C:14]([O:18][CH3:19])=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C:20]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:10]=2)[CH:6]=[C:5]1[C:39]([O:41][CH:43]([CH3:45])[CH3:44])=[O:40])([CH3:3])[CH3:2]
Reactant: COc1nccc2c1c(-c1cc(C(=O)O)n(C(C)C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nccc2c1c(-c1cc(C(=O)OC(C)C)n(C(C)C)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 46.2 %

Procedure:
A mixture of 1-isopropyl-4-(4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-1H-pyrrole-2-carboxylic acid (200 mg, 0.37 mmol), 2-iodopropane (310 mg, 1.80 mmol), Cs2CO3 (360 mg, 1.1 mmol) in THF (50 mL) was stirred at reflux for 6 hours. After cooling down, ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was separated and washed by water (30 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a yellowish oil (100 mg).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[C:9]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:42][C:43](OC(C)=O)=[O:44]>C(Cl)Cl>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:43](=[O:44])[CH3:42])[CH2:6]3)=[N:8][C:9]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-[3-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.237 mmol, 100 mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83 μL) and Ac2O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution was warmed to rt slowly and stirred under N2 for 1.5 h. The reaction was quenched with water (3 mL), diluted with methylene chloride (20 mL), washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flush column chromatography (Jones Flashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH3) in DCM, yielding the title compound as a light yellow solid. The sample was recrystallized from DCM (minimal amount) and EtOAc. The final product was obtained as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.43-8.42 (m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66 (m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH+]; HPLC: tR=2.06 min (OpenLynx, polar 5 min).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: COc1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(OCCCOc2ccc(C[C@H](OC)C(=O)O)cc2)c1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C20H24O6 [M+H]+: 361.4.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: Cc1ccc(-n2cccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 460 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3([C:17](O)=[O:18])[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([O:30][C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][C:24]=2[N:25]=1.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:37])[C:17]([C:14]1([NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:20][C:21]4[S:22][C:23]5[CH:29]=[C:28]([O:30][C:31]([F:34])([F:32])[F:33])[CH:27]=[CH:26][C:24]=5[N:25]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:15][CH2:16]1)=[O:18]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC3(C(=O)O)CC3)ccc21
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)CC1
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1-dimethylcarbamoyl-cyclopropyl)-amide (48 mg) was prepared by following General Procedure F using 1-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylic acid (49 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 520 [M+2]. 1H NMR (DMSO-d6, 400 MHz): δ 8.92 (s, 1H), 8.06 (s, 1H), 7.91 (m, 1H), 7.72 (d, 1H), 7.60 (br, 1H), 7.46 (d, 1H), 7.33 (d, 1H), 7.24 (m, 1H), 3.66 (s, 3H), 2.87 (d, 6H), 1.26 (t, 2H), and 1.01 (t, 2H).
Reaction SMILES: [CH:1]([O-:5])([O-])[O:2][CH3:3].F[C:7](F)(C(F)F)COC1C=CC(C(NCCOC2C=CC(CC(OC3C=CC(C(C)C)=CC=3)C(O)=O)=CC=2)=O)=CN=1.C([C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([O:63][CH3:64])=[O:62])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1)=O>CO>[CH3:7][O:5][CH:1]([O:2][CH3:3])[C:49]1[CH:50]=[CH:51][C:52]([C:55]2[CH:56]=[CH:57][C:58]([C:61]([O:63][CH3:64])=[O:62])=[CH:59][CH:60]=2)=[CH:53][CH:54]=1
Reactant: COC([O-])[O-]
Reactant: COC(=O)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(OCC(F)(F)C(F)F)nc3)cc2)C(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc(C(OC)OC)cc2)cc1
Reaction time: 14 h

Procedure:
Methyl orthoformate (4.55 ml) and amberlyst 15 (200 mg) were added to a solution of methyl 4′-formylbiphenyl-4-carboxylate (2.00 g) in methanol (20 ml). The mixture was allowed to stand at ambient temperature for 14 hours. The amberlyst was removed by filtration and the filtrate was concentrated under reduced pressure. Excess methyl orthoformate was azeotropicaly evaporated off with toluene.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[CH3:30][N:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH:36]=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:36][C:32]3[N:31]([CH3:30])[CH:35]=[CH:34][CH:33]=3)=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: Cn1cccc1C=O
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2cccn2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2cccn2C)c1

Procedure:
To a solution of hydroxyamine 55 (0.80 g, 2 mmol) in anhydrous ethyl alcohol (5 mL) and toluene (20 mL) was added 1-methyl-2-pyrrolecarboxaldehyde (66) (0.22 g, 2 mmol) and Na2SO4 (0.30 g). The resulting mixture was heated at reflux for 48 h. The mixture was diluted with dichloromethane (100 mL) and dried (MgSO4), and the solvent was removed with a rotary evaporator. The crude product was purified by flash chromatography with 9:1 ethyl acetate/methanol as the eluant to obtain 0.40 g (0.8 mmol, 40%) of 77 as a light yellow solid: mp 173°-175° C.; IR (CH2Cl2) 3440, 2940, 1695, 1622, 1575, 1470, 1300, 1212, 1100 cm-1 ; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.26 (s, 6H), 3.31 (s, 3H), 3.55 (t, J=4.8 Hz, 2H), 3.71 (s, 3H), 4.11-4.20 (m, 2H), 4.94 (septet, J=6.2 Hz, 1H), 5.08 (s, 1H), 6.30-7.98 (m, 9H); 13C NMR (CDCl3) δ 19.17, 19.32, 22.01, 22.23, 34.34, 39.98, 58.79, 62.76, 67.04, 70.71, 102.63, 103.45, 109.56, 117.39, 118.95, 121.24, 124.21, 125.59, 128.01, 128.23, 129.62, 145.20, 146.02, 148.30, 149.91, 167.12, 167.60; mass spectrum, m/e (relative intensity) 495 (M+, 3.1), 481 (15.5), 296 (100), 254 (86.1), 184 (90.2), 108 (48.3); high resolution mass spectrum, m/e 495.2362 (calcd. for C27H33N3O6, 495.2369).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][CH:44]([O:47][CH2:48][CH:49]=[CH2:50])[CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:42][CH2:43][CH:44]([O:47][CH2:48][CH:49]=[CH2:50])[CH2:45][CH2:46]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c(CCC)n3ncnc23)CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.41 g), sodium hydrogen carbonate (0.66 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.077 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.065 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 56%).