Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:17]([CH2:19][NH2:20])[OH:18]>CCOC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]2[N:7]=[C:2]([NH:20][CH2:19][CH2:17][OH:18])[CH:3]=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: NCCO
Reactant: COc1ccc(Nc2cccc(Cl)n2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2cccc(NCCO)n2)cc1
Temperature: 25 °C
Yield: 73 %

Procedure:
190 mg of 6-chloro-N-(4-methoxyphenyl)pyridin-2-amine were mixed with 397 mg of ethanolamine and the mixture obtained was heated in a screw cap vial under argon at 150° C. for 3 days. The mixture obtained was cooled to r.t. and 5 mL of EtOAc were added, The mixture obtained was extracted with 5 mL of EtOAc for three times, the phases were separated, the organic phase was dried and from the dry mixture obtained solvent was evaporated off. The evaporation residue obtained was subjected to flash column chromatography (EtOAc:PE 3:1). 2-(6-(4-Methoxyphenylamino)pyridin-2-ylamino)ethan-1-ol was obtained in the form of a brown oil.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8]>CO.[OH-].[Na+]>[CH2:12]([S:11][CH:4]([C:3]([OH:19])=[O:2])[NH:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)C(C)C)SCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)NC(SCc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 94.2 %

Procedure:
To a solution of Compound (3) (128.6 g; 458 mmol) in methanol (1400 ml), 1N aqueous sodium hydroxide (504 ml) was dropwise added while cooling at 0° C., and the resultant mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours, followed by concentration. The residue was diluted with a slight amount of water and washed with ether three times. The aqueous layer was collected, adjusted to pH 3 with 5% aqueous citric acid while cooling and extracted with ethyl acetate three times. The organic layer was washed with a saturated aqueous solution of sodium chloride three times, dried over anhydrous sodium sulfate and concentrated to give crude crystals. Recrystallization of said crude crystals from a mixture of ethyl acetate and petroleum ether gave Compound (4) (115.3 g; yield, 94%).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22]([CH3:24])=O)[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[NH:25]([C:27]([NH:29][C:30]1[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1)=[S:28])[NH2:26]>Cl.O>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22](=[N:26][NH:25][C:27]([NH:29][C:30]3[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=3)=[S:28])[CH3:24])[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(NC(=S)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Dimethylformamide (1.3 ml) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (59 mg, 0.26 mmol) synthesized in Reference Synthetic Example 57, and the mixture was stirred overnight at room temperature. Water was added, and the precipitated solid was filtered. The obtained solid was extracted with chloroform, dried over anhydrous sodium sulfate. The organic layer was concentrated, and purified with a silica gel column chromatography (chloroform/methanol=95/5) to obtain the desired product as a pale yellow solid (112 mg, yield 90%).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH3:17])[CH:3]=1>CCO.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH3:17])=[C:5]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cc(N)c(F)cc1C
Yield: 89.6 %

Procedure:
A solution of ethyl 2-(4-fluoro-2-methyl-5-nitrophenyl)acetate (16.79 g, 69.6 mmol) in EtOH (60 mL) was treated with 10% Pd/C (50% wet, 7.41 g, 3.48 mmol) and hydrogenated (3.5 atm) for 2 h. The solids were removed via filtration through diatomaceous earth, rinsed with EtOH and the filtrate was concentrated to afford ethyl 2-(5-amino-4-fluoro-2-methylphenyl)acetate (13.18 g, 90% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6): δ 6.80 (d, J=12.4 Hz, 1H), 6.59 (d, J=9.6 Hz, 1H), 4.86 (s, 2H), 4.05 (q, J=7.2 Hz, 2H), 3.46 (s, 2H), 2.05 (s, 3H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 212.2 (M+H)+.
Reaction SMILES: C(OC(=O)C[C@@H](NC(OC(C)(C)C)=O)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.[CH2:33]([O:40][C:41](=[O:66])[CH2:42][C@@H:43]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)[CH:48]=1)[C:44](O)=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[NH2:67][C@H:68]([C:73]1[NH:74][CH:75]=[CH:76][N:77]=1)[CH2:69][CH:70]([CH3:72])[CH3:71].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:33]([O:40][C:41](=[O:66])[CH2:42][C@@H:43]([C:47]1[CH:51]=[CH:50][N:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]#[N:65])=[CH:62][CH:63]=3)=[CH:54][CH:53]=2)[CH:48]=1)[C:44]([NH:67][C@H:68]([C:73]1[NH:77][CH:76]=[CH:75][N:74]=1)[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@H](N)c1ncc[nH]1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc([C@H](CC(=O)OCc4ccccc4)C(=O)O)c3)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@@H](CC(=O)OCc1ccccc1)c1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1)c1ncc[nH]1
Yield: 49 %

Procedure:
According to the procedure described in Example 1(b) for the preparation of 3(R)-t-butoxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, 2(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]succinic acid 4-benzyl ester (prepared as described in Example 14(b)) and 2-(1(S)-amino-3-methyl-butyl)-imidazole (see Chen, J. J.; Zhang, Y.; Hammond, S.; Dewdney, N.: Ho, T.; Browner, M. F.; Castelhano, A. L., submitted for publication; and Abel-Meguid, S. S.; Metcalf B. W.; Caw, T. J.; DeMarsh, P.; Des Jarlais, R. L.; Fisher, S.; Green, D. W.; et al. Biochemistry, 1994, 33, 11671-11677) were coupled with TBTU to provide a 49% yield of 3(S)-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-N-[1(S)-(1H-imidazol-2-yl)-3-methylbutyl]succinamic acid benzyl ester: mp 186-188° C. (dec); 1HNMR (DMSO-d6) δ 11.79 (s, 1H), 8.40 (d, 1H, J=8.5 Hz), 7.92 (s, 4H), 7.85 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.34 (s, 5 H), 6.97 (s, 1H), 6.84 (s, 1H), 6.20 (s, 1H), 5.13-5.00 (m, 3H), 3.96 (dd, 1H, J=9.9, 5.5 Hz), 2.99 (dd, 1H, J=16.4, 10.8 Hz), 2.78 (dd, 1H, J=16.4, 5.0 Hz), 1.67-1.60 (m, 2H), 1.55-1.45 (m, 1H), 0.85 (d, 3H, J=6.6 Hz), 0.81 (d, 3H, J=6.3 Hz); Anal. Calculated for C36H35N5O3•H2O: C, 71.62; H, 6.18; N, 11.60. Found: C, 71.50,71.45; H, 5.97, 6.01; N, 11.51, 11.48.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Cl:27][C:28]1[N:35]2[C:31]([S:32][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:34]2)=[C:30]([C:49]([C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:50])[N:29]=1>>[Cl:27][C:28]1[N:35]2[C:31]([S:32][C:33]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[CH:34]2)=[C:30]([C:49]([C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:50])[N:29]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(Cl)nc(C(=O)c3cccnc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4c(Cl)nc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Yield: 89.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-chloro-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (712 mg) was prepared in the same manner as in step a) of Example 1, except that 474 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 730 mg of 5-chloro-7-(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOCC>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccoc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Fc1ccc(Cc2ccco2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 0° C. solution of furan (13.6 g, 0.20 mol) in a mixture of anhydrous ether (230 mL) and anhydrous THF (70 mL) under nitrogen was added a 2.5M solution of n-butyllithium in hexane (54.0 mL, 0.134 mol). The mixture was stirred at 0° C. for 1.5 hours and then transferred by cannula to a stirred -78° C. solution of 4-fluorobenzyl bromide (23.6 g, 0.125 mol) and tetrakis(triphenylphosphine)palladium (0) (1.25 g, 0.001 mol) in anhydrous THF (200 mL). The transfer was made under nitrogen over a period of 30-40 minutes. The reaction mixture was stirred at ambient temperature overnight, saturated aqueous solution of ammonium chloride was added and the mixture extracted with ether. The ether layer was dried (MgSO4), concentrated in vacuo and the residue distilled at reduced pressure to give the title compound as a colorless oil (17.89 g, 81%). b.p. 57°-62° C. at 0.5-0.7 mm-Hg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12.[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:15]1>ClCCl>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH2:15][C@H:14]2[CH3:13])=[C:4]2[N:9]=[CH:10][CH:11]=[CH:12][C:3]=12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: Clc1nnc(Cl)c2ncccc12
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1c1nnc(Cl)c2cccnc12
Temperature: 100 °C
Yield: 43.5 %

Procedure:
To a reaction vial was added 5,8-dichloropyrido[2,3-d]pyridazine 78 (165 mg, 825 μmol) and (R)-(3-methylpiperazin-1-yl)(phenyl)methanone (337 mg, 1.65 mmol). The mixture was heated to 100° C. for 2 h. After cooling to room temperature, the resultant glassy product was dissolved in dichloromethane (40 mL) and washed with 1×5 mL NaHCO3 and 1×5 mL of brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel column chromatography using a gradient of 70% ethyl acetate in hexanes to 90% EtOAc in hexanes afforded the regioisomeric products. The first eluting product (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (132 mg, 44% yield) was the major product, the second eluting product (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (74 mg, 24% yield) was the minor product. Data for 79: 1H-NMR (400 MHz, CDCl3): δ 9.10 (brs, 1H), 8.47 (dd, J=8.2, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 5.46 (br m, 1H), 4.97-4.40 (series of m, 2H), 3.99-3.20 (series of m, 4H), 1.40 (br m, 3H). MS 367.1 (calc'd) 368.0 (M+H, found). Data for (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone: 1H-NMR (400 MHz, CDCl3): δ 9.27 (dd, J=4.3, 1.6, 1H), 8.39 (J=8.6, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 7.45 (s, 5H), 4.31 (br s, 1H), 4.11 (br s, 1H), 2.68 (m, 5H), 1.27 (br s, 3H). MS 367.1 (calc'd) 368.0 (M+H, found).
Reaction SMILES: C([Li])CCC.O1[C@@H:22]2[C@@:7]1([CH3:42])[CH:8]=[CH:9][C:10](=[O:41])[C@H:11]([CH3:40])[C@H:12]([OH:39])[C@@H:13]([CH3:38])[C:14](=[O:37])[C:15]([CH3:36])([CH3:35])[C@@H:16]([OH:34])[CH2:17][C:18](=[O:33])[N:19]([CH3:32])[C@H:20]([C:23]([CH3:31])=[CH:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1)[CH2:21]2.C([O-])(O)=O.[Na+]>O1CCCC1.CCCCCC.O.[W](Cl)(Cl)(Cl)(Cl)(Cl)Cl>[OH:34][CH:16]1[C:15]([CH3:36])([CH3:35])[C:14](=[O:37])[CH:13]([CH3:38])[CH:12]([OH:39])[CH:11]([CH3:40])[C:10](=[O:41])[CH:9]=[CH:8][CH:7]([CH3:42])[CH2:22][CH2:21][CH:20]([C:23]([CH3:31])=[CH:24][C:25]2[N:26]=[C:27]([CH3:30])[S:28][CH:29]=2)[N:19]([CH3:32])[C:18](=[O:33])[CH2:17]1
Reactant: CC(=Cc1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)C=CC(=O)[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1C
Agent: Cl[W](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=Cc1csc(C)n1)C1CCC(C)C=CC(=O)C(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)N1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tungsten hexachloride (0.76 g) in tetrahydrofuran (20 mL) at −78° C. is treated with a 1.6 M solution of n-butyllithium in hexane (2.5 mL). The mixture is allowed to warm to ambient temperature over 20 minutes. A 13.8 mL portion of the resulting green solution is added to a solution of (4S,7R,8S,9R, 13R, 14S, 16S)-13,14-epoxy-4,8-dihydroxy-2,6,10-trioxo-1,5,5,7,9,13-hexamethyl-16-(1-(2-methylthiazol-4-yl)propen-2-yl)-1-aza-11-cyclohexadecene (370 mg) in 2 mL of tetrahydrofuran at ambient temperature. After 30 min, the reaction is cooled to 0° C. and treated with sat. NaHCO3 (10 mL). The mixture is diluted with water and extracted with CH2Cl2. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([CH:14]([CH3:16])[CH3:15])=[C:8]([CH:13]=1)[O:9][CH2:10][C:11]#[N:12].[CH:19]([O:21][CH2:22]C)=O.IC>>[Br:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([CH:14]([CH3:16])[CH3:15])=[C:8]([CH:13]=1)[O:9][C:10](=[CH:19][O:21][CH3:22])[C:11]#[N:12]
Reactant: CCOC=O
Reactant: COc1cc(C(C)C)c(OCC#N)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: COC=C(C#N)Oc1cc(Br)c(OC)cc1C(C)C
Temperature: 80 °C
Yield: 48.2 %

Procedure:
Sodium hydride (0.122 g, 5.0 mmol, 60% w/w) was washed with dry hexanes and evaporated under a stream of nitrogen. 10 mL THF was added and the mixture was cooled to 0° C. (5-Bromo-2-isopropyl-4-methoxy-phenoxy)-acetonitrile (0.577 g, 2.03 mmol) was added in portions. After 30 min ethyl formate (4.9 mL, 60.9 mmol) was added and the solution was warmed to 80° C. After 4.5 hours the mixture was cooled and 5.0 mL iodomethane was added in one portion. After 16 hours the solution was quenched with H2O, concentrated in vacuo, extracted with ethyl acetate, washed with H2O and then washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (9:1 hexane/ethyl acetate) afforded 2-(5-bromo-2-isopropyl-4-methoxy-phenoxy)-3-methoxy-acrylonitrile (0.319 g, 48%) as a white solid.
Reaction SMILES: [CH2:1]([NH:7][C@H:8]([C:13]([OH:15])=O)[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[Br:50][C:51]1[CH:52]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][O:64][C@H:65]3[CH2:69][NH2+:68][C@H:67]([C:70]([O:72][CH3:73])=[O:71])[CH2:66]3)[CH:58]=2)[CH:54]=[CH:55][CH:56]=1>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([NH:7][C@H:8]([C:13]([N:68]1[CH2:69][C@H:65]([O:64][CH2:63][C:59]2[CH:58]=[C:57]([C:53]3[CH:54]=[CH:55][CH:56]=[C:51]([Br:50])[CH:52]=3)[CH:62]=[CH:61][CH:60]=2)[CH2:66][C@H:67]1[C:70]([O:72][CH3:73])=[O:71])=[O:15])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)C[NH2+]1
Reactant: C=CCCCCN[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCCCN[C@H](C(=O)N1C[C@H](OCc2cccc(-c3cccc(Br)c3)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
N-hex-5-en-1-yl-3-methyl-L-valine (1.2 eq.), DIPEA (3.7 eq.) and HATU (1.2 eq.) were sequentially added to a 0.10 M solution of (2S,4R)-4-[(3′-bromobiphenyl-3-yl)methoxy]-2-(methoxycarbonyl)pyrrolidinium chloride in DMF. The reaction mixture was stirred at RT overnight then it was diluted with H2O/EtOAc and extracted. The collected organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography (SiO2, PE:EtOAc with EtOAc from 30 to 100%) to afford the title compound 101 as a solid (50%). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.85 (bs, 1H), 7.69 (d, J 7.8, 1H), 7.66-7.58 (m, 3H), 7.51-7.43 (m, 2H), 7.37 (d, J 7.8, 1H), 5.76-5.64 (m, 1H), 4.97-4.87 (m, 2H), 4.63 (s, 2H), 4.45 (t, J 8.6, 1H), 4.31 (bs, 1H), 4.07 (d, J 11.7, 1H), 3.66 (s, 3H), 3.73-3.55 (m, 2H), 2.50-2.41 (m, 1H), 2.40-2.32 (m, 1H), 2.31-2.23 (m, 1H), 2.08-1.96 (m, 1H), 1.94-1.85 (m, 2H), 1.34-1.18 (m, 3H), 0.96 (s, 9H), 0.94-0.85 (m, 2H). MS (ES+) m/z 585, 587 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][Si](Cl)(C)C>CO>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([O:9][CH3:12])=[O:8]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methylsalicylic acid (7.24 g) in methanol (250 ml) was added trimethylsilyl chloride (60 ml). The mixture was heated at reflux for 2 hours and stirred at room temperature overnight. A further 60 ml trimethylsilyl chloride was added and the mixture heated at reflux for 6 hours. The mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated to give the crude product. Yield 5.87 g. Used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[C:5]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:54]([NH:57][NH2:58])(=[O:56])[CH3:55]>CN(C)C=O.O>[C:54]([NH:57][NH:58][C:9]([C:7]1[CH:6]=[C:5]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:4]=[C:3]([O:2][CH3:1])[N:8]=1)=[O:11])(=[O:56])[CH3:55]
Reactant: COc1ccc(CCNc2cc(C(=O)O)nc(OC)n2)cc1
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CCNc2cc(C(=O)NNC(C)=O)nc(OC)n2)cc1
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
To a solution of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid [100 mg, 0.33 mmol, Intermediate (56)] in dimethylformamide (1 mL) is added N,N-diisopropylethylamine (145 μL, 0.83 mmol) followed by TBTU (128 mg, 0.4 mmol). Stirred the reaction mixture for 5 minutes before adding acetic hydrazide (37 mg, 0.5 mmol) and continued stirring the reaction mixture overnight at ambient temperature. The reaction mixture is poured into water (25 mL) and subsequently extracted three times with 25 mL ethyl acetate. The combined organic extracts are washed three times with 25 mL water, with 25 mL brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The material obtained is subjected to flash column chromatography on silica (10 g) eluting with 0 to 5% MeOH in DCM gradient to afford 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg). A mixture of 2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidine-4-carboxylic acid N′-acetyl-hydrazide (42 mg, 0.12 mmol), p-toluenesulfonylchloride (34 mg, 0.18 mmol) and PS-BEMP (218 mg, 0.48 mmol) in THF (1.5 mL) is irradiated in a microwave to 140° C. for 6 minutes. The material is filtered and absorbed onto silica gel and subjected to flash column chromatography on silica gel eluting with 10 to 50% EtOAc in heptane gradient to afford [2-methoxy-6-(5-methyl-[1,3,4]oxadiazol-2-yl)-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [25.1 mg, 63%, Example 44]. LCMS: RT=2.64 minutes, MS: 342 (M+H). IC50=55 nM
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10](CNCC(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(O)(=O)CNC(C1C=CC=CC=1)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCC(CNCC(c3ccccc3)c3ccccc3)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CNC(=O)c1ccccc1
Solvent: ClCCl
Product: Clc1ccc(CN2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-{N-(2,2-diphenylethyl)aminomethyl}piperidine (0.084 mmol) in CH2Cl2 was treated with hippuric acid (1.1 equiv.), HBTU (1.1 equiv.), HOBt (1.1 equiv.). The reaction mixture was stirred at 40° C. for 24 h. General workup and preparative TLC (SiO2) afforded 4-{N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl)}-1-(4-chlorobenzyl)piperidine (Compound No. 524) (8.5 mg, 17%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 580 (M++H, C36H38ClN3O2).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=O.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[N:12][CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: CN1CCC(N)CC1
Solvent: CCO
Product: CN1CCC(N=Cc2nc3ccccc3[nH]2)CC1

Procedure:
1H-Benzimidazole-2-carboxaldehyde (781 mg, can be prepared according to Fegy, K. Angewandte Chemie Int Ed, 1998, vol. 37, 1270-1273), 4-amino-1-methylpiperidine (781 mg) and 4 Å molecular sieves (15 g) in ethanol (100 mL) are heated under reflux for 4 h. The mixture is then filtered and the filtrate concentrated under reduced pressure to yield (1H-benzimidazol-2-ylmethylene)(1-methylpiperidin-4-yl)amine as a beige solid.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[N:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>>[Br:37][C:34]1[CH:33]=[N:32][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:36][CH:35]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ncc(Br)cn2)cc1
Yield: 37 %

Procedure:
Condensation of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (5.16 g; 12.6 mmol) with 2,5-dibromo-pyrimidine (3.0 g; 10.5 mmol) as per general procedure E (conditions: 1.1 eq DIEA, 210C, 2 hr) provided after chromatography the intermediate ethyl 2-[4-(2-{(5-bromopyrimidin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (2.2 g; 37% yield).