Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15]OC(=O)C)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(=O)([O-])O.[Na+].[CH3:30][C:31]1[N+:36]([O-:37])=[N:35][C:34]([SH:38])=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O>>[C:1]([NH:7][CH:8]1[C:23](=[O:24])[N:10]2[C:11]([C:20]([OH:22])=[O:21])=[C:12]([CH2:15][S:38][C:34]3[N:35]=[N+:36]([O-:37])[C:31]([CH3:30])=[CH:32][CH:33]=3)[CH2:13][S:14][C@H:9]12)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: Cc1ccc(S)n[n+]1[O-]
Reactant: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3ccc(C)[n+]([O-])n3)CS[C@H]12

Procedure:
A mixture of 0.356 g. of 7-acetoacetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, 0.84 g. of sodium hydrogen carbonate, 0.156 g. of 6-methyl-1-oxidopyridazine-3-thiol and 20 ml. of a phosphate buffer of pH 6.4 is heated at 60° C for 7.5 hours. After cooling, the reaction mixture is washed with ethyl acetate, brought to pH 2 with 50 % phosphoric acid, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer is dried over magnesium sulfate and concentrated under reduced pressure. The concentrate is allowed to stand under cooling with ice. The resultant crystals are loosened with the addition of ethyl ether, recovered by suction-filtration, washed with hexane and dried. The procedure gives 7-acetoacetamido-3-(6-methyl-1-oxidopyridazin-3-yl)thiomethyl-3-cephem-4-carboxylic acid as crystals melting at 85°-87° C (decomp.). Yield 0.18 g. (41 %).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:16]([C:15]1[CH:14]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)O)c1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of compound 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)benzoic acid (100 mg, 0.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (70 mg, 0.34 mmol), BOPCl (100 mg, 0.41 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at 25° C. for 4 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and the residue was purified by prep-TLC to give the title product which was used directly in next step (150 mg, Yield 93%). LCMS (m/z): 480.2 (M+1).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])=[O:9])C.Cl>O>[O:30]=[C:29]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:31])[N:21]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)csc1N1C(=O)c2ccccc2C1=O
Yield: 92 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-phenyl-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 1, Part C). The mixture was heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 92% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:22][CH2:21]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CC(CCl)CN1CCOCC1
Agent: Cl
Product: CC(COc1c(-c2ccccc2)c(=O)oc2ccccc12)CN1CCOCC1
Yield: 82.5 %

Procedure:
This compound is prepared according to the method of Example 8 from 14.3 g. (0.06 mol) of 4-hydroxy-3-phenyl-coumarin and 16.7 g. (0.078 mol) of 3-morpholino-2-methyl-1-chloropropane hydrochloride. After recrystallisation from ethanol, 18.8 g. are obtained. Yield 82.5% (theoretical yield 22.8 g.); M.P. 113° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:35])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[N:3]=1.CO.[ClH:46].O1CCOCC1>>[ClH:46].[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:17]=[CH:18][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:20][CH:21]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:35])[N:4]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[CH:38]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)c2C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(Cn2nc(C)c(-c3c[nH]c4ncc(-c5ccc(N6CCNCC6)cc5)cc34)c2C)c1
Yield: 63 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (20 mg, 0.034 mmol) was deprotected in methanol/1,4-dioxane HCl in (0.3/1 ml). This afforded 10 mg (63% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.74 (s, 1H), 8.65 (s, 1H), 7.86 (s, 1H), 7.71-7.69 (d, 2H), 7.32-7.29 (t, 1H), 7.20-7.15 (m, 4H), 7.09-7.07 (d, 1H), 5.51 (s, 2H), 3.53-3.50 (m, 4H), 3.41-3.38 (m, 4H), 2.36-2.34 (m, 9H). MS: m/z=477.2 (M+1) HPLC 98.14% (method B).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:27][CH:28]3[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]3)[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.[CH:42]1(B(O)O)[CH2:44][CH2:43]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1(C)C=CC=CC=1.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>[CH:42]1([C:2]2[N:6]3[N:7]=[C:8]([NH:27][CH:28]4[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]4)[CH:9]=[C:10]([N:11]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:5]3=[N:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: OB(O)C1CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(Br)cnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(CN(c2ccccc2)c2cc(NC3CCC(NC(=O)OC(C)(C)C)CC3)nn3c(C4CC4)cnc23)cc1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
tert-Butyl 4-(3-bromo-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate (30 mg, 0.048 mmol) from (1a) and cyclopropylboronic acid (10 mg, 0.090 mmol) in toluene were purged with argon for 15 min, then aq. K3PO4 (2M, 0.06 mL), EtOH (0.04 mL) and tetrakis(triphenylphosphine)palladium(0) were added sequentially. The mixture was heated at 120° C. for 20 h. After cooling to room temperature, the mixture was partitioned between EtOAc (20 mL) and water (5 mL) and the organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by reverse phase preparative HPLC to provide tert-butyl 4-(3-cyclopropyl-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazin-6-ylamino)cyclohexylcarbamate as a cream colored oil (4.3 mg, 15%) LCMS [M+H]+ 583.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[CH3:18].Br>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH3:18]
Reactant: COc1ccc(C2(C)Cc3cc(OCC(=O)O)c(Cl)c(Cl)c3C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1(c2ccc(O)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C

Procedure:
A stirred mixture of [1-oxo-2-(4-methoxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid (1.80 g., 0.0046 mole), Example 8, Step E, 48% hydrobromic acid (50 ml.) and acetic acid (50 ml.) is heated at reflux for one hour, then poured into crushed ice-water (800 ml.) to precipitate 900 mg. of [1-oxo-2-(4-hydroxyphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]-acetic acid which melts at 220°-222° C. after crystallization from acetic acid:water, 1:1, and nitromethane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20]C=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([OH:9])=O.CC1N=C(N2C=C(CC(C3C=CC=CC=3)C)N=N2)SC=1C(O)=O.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][NH2:54])[CH:48]=1>>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=[N:11]2)[S:5][C:6]=1[C:7]([NH:54][CH2:53][C:49]1[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=1)=[O:9]
Reactant: NCc1cccnc1
Reactant: Cc1nc(-n2cc(CCCc3ccccc3)nn2)sc1C(=O)O
Agent: Cc1nc(-n2cc(CC(C)c3ccccc3)nn2)sc1C(=O)O
Product: Cc1nc(-n2cc(CCc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 25 %

Procedure:
Following the procedure as described in Example 14, making variations as necessary to replace 4-methyl-2-(4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid with 4-methyl-2-(4-(2-phenylpropyl)-1H-1,2,3-triazol-1-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 25% yield: mp 114-116° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59-8.53 (m, 2H), 8.02 (s, 1H), 7.75-7.72 (m, 1H), 7.33-7.18 (m, 6H), 5.57 (m, 1H), 4.64 (d, J=5.9 Hz, 2H), 3.13-3.02 (m, 4H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 155.7, 153.9, 149.0, 148.9, 148.6, 140.5, 135.9, 133.6, 128.5, 128.4, 126.3, 123.8, 123.4, 118.6, 41.7, 35.0, 27.2, 17.5; MS (ES+) m/z 405.1 (M+1).
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[C:5]=1[OH:19].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:33]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[C:5]=1[OH:19])=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: CCS(=O)(=O)c1cc(C(C)(C)C)cc(CN)c1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CCS(=O)(=O)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
0.615 g of 2-aminomethyl-4-(1,1-dimethylethyl)-6-ethylsulfonylphenol hydrochloride are reacted with 0.36 g of urotropine in 8 ml of trifluoroacetic acid to give 2-formyl-4-(1,1-dimethylethyl)-6-ethylsulfonylphenol in analogy to Example 1.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl.CO>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13](=[O:36])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH:35]=[C:23]2[N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:26][CH2:27][C:22]2=[N:21]1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCN2Cc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2c(n1)CCCN2Cc1ccccc1

Procedure:
Oxidation of N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-2-(4-benzyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridin-2-yl)nicotinamide (150 mg, 0.294 mmol) as described in example 2.4 and purification by chromatography over silica gel (eluent: dichloromethane/methanol) afforded the title compound as an amorpous solid; 11 mg, ESI-MS [M+H]+: 509.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.62 (m, 1H), 8.35 (m, 2H), 7.76 (m, 1H), 7.50 (m, 1H), 7.35-7.12 (m, 12H), 5.85 (s, 1H), 4.36 (m, 1H), 4.20 (s, 2H), 3.20 (m, 2H), 2.93 (m, 2H), 2.71 (m, 3H), 1.94 (m, 2H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([CH3:47])[CH2:12][C@H:13]([N:17]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14](O)=[O:15].[NH2:48][C@H:49]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[CH3:10][CH:11]([CH3:47])[CH2:12][C@H:13]([N:17]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:18](=[O:38])[C@@H:19]([NH:28][C:29](=[O:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([NH:48][C@@H:49]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:15]
Reactant: CC(C)C[C@@H](C(=O)O)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)N(COC(=O)C(C)(C)C)C(=O)[C@H](CCc1ccccc1)NC(=O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
Referring to FIG. 45, DIPEA (270 μL, 1.6 mmol, 2.5 eq) was added to a mixture of acid (S)-4-methyl-2-((S)-2-(2-morpholinoacetamido)-4-phenyl-N-((pivaloyloxy)methyl)butanamido)pentanoic acid (345 mg, 0.64 mmol), H-Phe-OBn (283 mg, 0.97 mmol, 1.5 eq) and HATU (370 mg, 0.97 mmol, 1.5 eq) in CH2Cl2 (10 mL) and the mixture was stirred for four hours at RT. The mixture was poured into water and extracted twice with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-80% EtOAc in heptanes) and product (330 mg, 67%) was isolated as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[C:36]=3[Cl:45])[CH2:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Li+].[Cl-]>CN(C=O)C>[ClH:45].[Cl:45][C:36]1[C:37]([C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:19]([CH2:20][CH:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:18][CH2:17][CH2:16][O:15][C:11]1[CH:10]=[C:9]([C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cl
Product: O=C(O)C1(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CCC1
Reaction time: 0.17 h

Procedure:
A solution of 1-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-cyclobutanecarboxylic acid methyl ester (40 mg, 0.06 mmol) in DMF (9 ml) was treated with LiCl (20 mg, 0.46 mmol). The resulting reaction mixture was heated to reflux overnight and concentrated under vacuum. The crude product was purified by HPLC (YMC CombiPrep ODS-A, 50×20 mm, 20 mL/min, A: acetonitrile B: water, A: 60 to 100% during 10 min, W detection at 254 nm) to give the title compound, the free amine as an oil (20 mg, 50%). MS m/e 622.2 (M+H)+. To a solution of the free amine in diethyl ether was added HCl in diethyl ether (1.0M) to precipitate the amine salt. The suspension was filtered and dried to give the title compound as a white solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22].[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH-:34])=[CH:31][CH:30]=1)#[N:28].[ClH:37]>>[NH2:1][C@@H:2]([C:9]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:11])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH-:34])=[CH:31][CH:30]=1)#[N:28].[ClH:37]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Agent: Cl
Agent: N#Cc1ccc(C[NH-])cc1
Product: N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1

Procedure:
Firstly H-(D)-Chg-Pro-p-cyanobenzylamide×HCl was prepared from Boc-(D)-Chg-OH and H-Pro-p-cyanobenzylamide×HCl as in Example 3.
Reaction SMILES: [CH3:1][C:2]1([C:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[S:21]C(C2(C)CCCCC2)=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[K+].O>CO.O1CCCC1>[SH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[NH:10][C:8]([C:2]1([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9]
Reactant: CC1(C(=O)Nc2c(SC(=O)C3(C)CCCCC3)ccc3ccccc23)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C(=O)Nc2c(S)ccc3ccccc23)CCCCC1
Reaction time: 1 h

Procedure:
The crude product obtained in step A) is dissolved in a mixture of methanol and tetra-hydrofuran (1:1). Then 3.5 mol equivalents of potassium hydroxide are added at room temperature and the mixture is stirred for 1 hour. Then water is added and the mixture is washed with n-hexane. The aqueous layer is then acidified by addition of KHSO4 and extracted with chloroform. The combined extracts are washed with water and brine, dried (Na2SO4) and concentrated to obtain the desired title compound.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:15]([CH3:21])[C:16]([O:18]CC)=O)[CH:8]=[CH:9][C:10]=1[O:11]C(=O)C)(=O)C.[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:22]([NH:28][C:16](=[O:18])[CH:15]([C:7]1[CH:8]=[CH:9][C:10]([OH:11])=[C:5]([OH:4])[CH:6]=1)[CH3:21])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN
Reactant: CCOC(=O)C(C)c1ccc(OC(C)=O)c(OC(C)=O)c1
Product: CCCCCCNC(=O)C(C)c1ccc(O)c(O)c1

Procedure:
Ethyl 3,4-diacetoxyphenylpropionate and n-hexylamine were used to obtain N-n-Hexyl-3,4-dihydroxyphenylpropionamide by carrying out the same procedures as described in Example 1.
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1([Hf+2:12]C2(CCCC)C=CC=C2)[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6].[C:22]([OH:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[C:22]([O-:28])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:3]([C:7]1([Hf+3:12])[CH:11]=[CH:10][CH:9]=[CH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC1([Hf+2]C2(CCCC)C=CC=C2)C=CC=C1
Reactant: CC(C)(C)C(=O)O
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)[O-]
Product: CCCCC1([Hf+3])C=CC=C1
Yield: 66 %

Procedure:
To a solution of bis(n-butylcyclopentadienyl)hafnium dichloride (0.500 g, 1.012 mmol ) and pivalic acid (0.330 g, 3.230 mmol ) in toluene (30 ml) at 50° C. was added triethylamine (0.363 g, 3.240 mmol ) with stirring. A white precipitate formed immediately which was removed by filtration. The title compound was isolated as a dark yellow oil in 66% yield by evaporating the solvent under vacuum. The title compound such prepared exhibit purity above 95% based on NMR results. 1H NMR (toluene-d8) δ 6.15 (m, 2H), 5.90 (m,2H), 2.67 (t,J=7.6 Hz, 2H), 1.54 (m, 2H), 1.31 (m, 2H), 1.13 (s, 27H), 0.88 (t, J=7.2 Hz, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:27]([O:26][C:22](=[O:25])[CH:23]=[CH:24][C:2]1[CH:14]=[CH:13][CH:12]=[C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH:3]=1)[CH3:28]
Reactant: C=CC(=O)OCC
Reactant: Ic1cccc(CN2CCOCC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1cccc(CN2CCOCC2)c1
Temperature: 80 °C
Yield: 79.8 %

Procedure:
To a solution of 4-(3-iodo-benzyl)-morpholine (3.44 g, 11.4 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (1.7 mL, 12.5 mmol), ethyl acrylate (4.1 mL, 45.4 mmol), tri-o-tolylphosphine (346 mg, 1.14 mmol) and palladium (II) acetate (127 mg, 0.57 mmol). The mixture was heated at 80° C. overnight. After concentration, the mixture was chromatographed on silica gel to afford Intermediate 172(a) as a colorless oil (2.37 g, 9.1 mmol) in 80% yield.
Reaction SMILES: ClC([O:4][C:5](Cl)(Cl)Cl)=O.[Cl:9][C:10]1[C:11]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH:27]([NH2:31])([CH2:29][CH3:30])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH:27]([NH:31][C:5]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:18])([F:19])[F:17])=[CH:13][N:12]=2)=[N:22]1)=[O:4])([CH2:29][CH3:30])[CH3:28]
Reactant: CCC(C)N
Reactant: Cc1cc(Oc2ncc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCC(C)NC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
Trichloromethyl chloroformate (0.49 g, 2.5 mmol) was added to a solution of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole (0.69 g, 2.5 mmol) in chloroform (10 ml) at 0° C., and while the mixture was allowed to have room temperature gradually, it was further stirred at room temperature for 3 hours. Sec-butylamine (0.22 g, 3.0 mmol) and potassium carbonate (0.42 g, 3.0 mmol) were added to the reaction mixture, and the mixture was stirred at 50° C. for 8 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with chloroform (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7), to give a colorless viscous substance of N-s-butyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.24 g, yield: 25.5%). 1H-NMR (CDCl3, TMS, ppm): δ 0.96 (t, J=7.5 Hz, 3H), 1.22 (d, J=6.6 Hz, 3H), 1.45-1.65 (m, 2H), 2.65 (s, 3H), 3.75-4.00 (m, 1H), 6.04 (s, 1H), 6.75-7.05 (m, 1H), 8.02 (d, J=1.8 Hz, 1H), 8.30-8.40 (m, 1H).