Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([C@@H](C2C=CN(C)N=2)N)=CC=1F.[F:17][C:18]1[CH:19]=[C:20]([C@@H:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[NH2:27])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[CH:34]1([CH2:37][NH:38][C:39]2[N:48]=[CH:47][C:46]3[C:41](=[CH:42][C:43]([C:50](O)=[O:51])=[CH:44][C:45]=3[F:49])[N:40]=2)[CH2:36][CH2:35]1>>[F:17][C:18]1[CH:19]=[C:20]([C@H:26]([NH:27][C:50]([C:43]2[CH:42]=[C:41]3[C:46]([CH:47]=[N:48][C:39]([NH:38][CH2:37][CH:34]4[CH2:35][CH2:36]4)=[N:40]3)=[C:45]([F:49])[CH:44]=2)=[O:51])[C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: O=C(O)c1cc(F)c2cnc(NCC3CC3)nc2c1
Reactant: COc1ccc([C@H](N)c2cnn(C)c2)cc1F
Agent: Cn1ccc([C@@H](N)c2ccc(Cl)c(F)c2)n1
Product: COc1ccc([C@H](NC(=O)c2cc(F)c3cnc(NCC4CC4)nc3c2)c2cnn(C)c2)cc1F

Procedure:
2-(Cyclopropylmethyl-amino)-5-fluoro-quinazoline-7-carboxylic acid [(S)-(3-fluoro-4-methoxy-phenyl)-(1-methyl-1H-pyrazol-4-yl)-methyl]-amide (I-60) was prepared analogously except 32b was replaced with 40f and 84b was replaced with 87c.
Reaction SMILES: [Li]CCCC.O1CC[NH:8][CH2:7]1.CO[B:13]([O:16]C)[O:14]C.C[Si](Cl)(C)C.[C:23]12([OH:34])[CH2:31][CH:27]([C:28]1([CH3:30])[CH3:29])[CH2:26][CH2:25][C:24]2([OH:33])[CH3:32].[CH3:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C1COCC1.CCOCC>[C:23]12([OH:34])[CH2:31][CH:27]([C:28]1([CH3:30])[CH3:29])[CH2:26][CH2:25][C:24]2([OH:33])[CH3:32].[CH3:30][C:28]1([CH3:29])[CH2:23][O:34][C:7]([C:37]2[CH:36]=[C:35]([B:13]([O-:14])[O-:16])[CH:40]=[CH:39][CH:38]=2)=[N:8]1
Reactant: COB(OC)OC
Reactant: C1COCN1
Reactant: CCCCCC
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cccc(B([O-])[O-])c2)=N1
Reaction time: 1.5 h
Yield: 54 %

Procedure:
n-BuLi (2.5 mL of a 2.5 M solution in hexane, 6.23 mmol) was added dropwise with stirring to a solution of 6 (1.51 g, 5.93 mmol) in THF (9.5 mL) at −78° C. under argon. After 30 min a solution of trimethylborate (0.7 mL, 5.93 mmol) in THF (2 mL) was added and the mixture stirred for 1.5 h; thereafter, the resulting yellow solution was quenched with TMSCl (0.75 mL, 5.93 mmol) and allowed to reach rt. After 1 h (+)-pinanediol (1.01 g, 5.93 mmol) dissolved in a minimum amount of anhydrous Et2O was added one portion to the solution, and then stirred overnight. The reaction mixture was partitioned in Et2O (16 mL) and H2O (10 mL) and the aqueous phase extracted with Et2O (2×10 mL). The combined organic phases were dried on MgSO4, filtered and concentrated to give an orange oil, which was purified by chromatography (7:3 EtPet/EtOAc) and crystallization (EtPet), affording 7 (1.14 g, 54%) as a white crystalline solid, mp 98-101° C., [α]D=+11.2 (c 1.5, CHCl3). IR (KBr): 1646 cm−1. 1H NMR (CDCl3): δ 0.81 (3H, s, pinanyl CH3), 1.22 (1H, d, J=10.5 Hz, pinanyl Hendo), 1.33 (3H, s, pinanyl CH3), 1.40 (6H, s, 2CH3), 1.50 (3H, s, pinanyl CH3), 1.5-2.5 (5H, m, pinanyl protons), 4.22 (2H, s, CH2O), 4.47 (1H, dd, J=8.8, 2.0 Hz, pinanyl CHOB), 7.43 (1H, t, J=7.7 Hz, H5 arom.), 7.92 (1H, dt, J=7.7, 1.5 Hz, H6 arom.), 8.05 (1H, dt, J=7.7, 1.5 Hz, H4 arom.), 8.43 (1H, br s, H2 arom.). 13C NMR (CDCl3): δ 24.4, 26.9, 27.5, 28.8 (2C), 29.1, 35.9, 38.6, 40.0, 51.9, 68.0, 78.8, 79.5, 86.8, 128.1, 131.2, 135.0, 137.8, 162.5, (CB and aromatic quaternary C not seen). EI-MS: m/z 353 (M+), 338 (base peak), 323, 282, 242, 202, 186, 130, 103, 67, 55. Anal. Calcd for C21H28NO3B: C, 71.39; H, 7.99; N 3.96. Found: C, 71.01; H, 8.65; N, 3.89.
Reaction SMILES: O=[C:2]([CH3:12])[CH:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5].Br.[NH2:14][NH2:15]>CCO.O>[CH3:12][C:2]1[NH:15][N:14]=[C:4]([NH2:5])[C:3]=1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C(C#N)c1cccnc1
Reactant: NN
Agent: Br
Solvent: CCO
Solvent: O
Product: Cc1[nH]nc(N)c1-c1cccnc1

Procedure:
3-Oxo-2-pyridin-3-yl-butyronitrile (step 1) (1.00 g, 6.49 mmol) was dissolved in EtOH (10 ml) and water (2 ml). Hydrazine hydrobromide (2.82 g, 24.97 mmol) was added and the reaction mixture was heated at reflux for 1 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc and sat. NaHCO3. The organic phase was washed with water and brine, dried (MgSO4), filtered and the solvent was removed in vacuo to afford the title compound which was used without further purification; 1H NMR (d6-DMSO, 400 MHz) δ 11.51 (1H, br), 8.60 m), 8.40 (1H, m), 7.72 (1 h, m), 7.39 (1H, m), 4.60 (2H, br), 2.19 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[S:10][C:11]([CH3:14])=[CH:12][CH:13]=3)=[N:6][C:5]2=[C:15]([C:17]([OH:19])=O)[CH:16]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:15]1[CH:16]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[S:10][C:11]([CH3:14])=[CH:12][CH:13]=4)=[N:6][C:5]=13)=[O:19])[CH2:46]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Cl)cc3o2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(C(=O)N[C@@H]4CN5CCC4CC5)cc(Cl)cc3o2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
A mixture of 6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxylic acid (41 mg, 0.14 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (35 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.08 mL, 0.56 mmol) was added. The resulting reaction mixture was stirred at room temperature for 4 h. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-2-(5-methylthiophen-2-yl)benzoxazole-4-carboxamide (30 mg, 55%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.43 (d, J=7.4 Hz, 1H), 8.12 (d, J=1.9 Hz, 1H), 7.74 (d, J=3.7 Hz, 1H), 7.64 (d, J=1.9 Hz, 1H), 6.90 (dd, J=3.7, 0.9 Hz, 1H), 4.33-4.29 (m, 1H), 3.54-3.47 (m, 1H), 3.15-3.03 (m, 2H), 2.95-2.90 (m, 2H), 2.85-2.79 (m, 1H), 2.61 (s, 3H), 2.15-2.05 (m, 2H), 1.86-1.76 (m, 2H), 1.75-1.65 (m, 1H); MS (ESI+) m/z 402 (M+H); HPLC>99% (AUC), tR=12.99 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH:19]1([NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:19]1([NH:22][C:23]([C:25]2[C:26]3[CH:34]=[CH:33][C:32]([O:35][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]6)=[O:12])[S:10][C:3]=45)=[CH:31][C:27]=3[S:28][C:29]=2[CH3:30])=[O:24])[CH2:21][CH2:20]1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)ccc2c1C(=O)NC1CC1
Yield: 65.8 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-hydroxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4a (113 mg, 0.40 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner as previously described for example 1 to give a yellow solid (130 mg, 66%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.46 Hz), 8.46 (1H, d, J=4.33 Hz), 8.06, 8.00 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.85 Hz), 7.33 (1H, dd, J=2.35, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 5.07 (1H, m), 4.38, 4.33 (1H, br s), 4.02-3.92 (2H, m), 3.67-3.44 (2H, m), 2.93-2.87 (1H, m), 2.57 (3H, s), 2.08-1.79 (2H, m), 0.76-0.70 (2H, m), 0.60-0.55 (2H, m).
Reaction SMILES: C(OC(C1C=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C:9]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:22][C:12]2[NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[N:15][C:11]=2[CH:10]=1)=O)C.[F:39][CH:40]([F:49])[O:41][C:42]1C(O)=CC=C[N:43]=1>>[F:39][CH:40]([F:49])[O:41][C:42]1[C:7]([O:8][C:9]2[C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:22][C:12]3[NH:13][C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[N:15][C:11]=3[CH:10]=2)=[CH:35][CH:36]=[CH:37][N:43]=1
Reactant: Oc1cccnc1OC(F)F
Reactant: CCOC(=O)c1ccccc1Oc1cc2nc(-c3ccccn3)[nH]c2cc1Oc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2OC(F)F)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 14 or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(4-methanesulfonyl-phenoxy)-2-nitro-phenylamine obtained in Example 14 and 2-difluoromethoxy-pyridin-3-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:11].S(=O)(=O)(O)O.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c(I)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(I)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
4-Chloro-3-iodo-benzoic acid (5.31 g, 18.8 mmol) was dissolved in methanol (50 mL) and concentrated sulfuric acid (3 mL) was carefully added. The solution was stirred at 80° C. for 4 hours, then cooled to room temperature and the volatile organics were removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and water (50 mL) and the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; 0-10% EtOAc in hexanes) to yield 5.32 g (95%) of the title compound as an oil. 1H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J=2.0 Hz, 1H), 7.96 (dd, J=8.4, 2.0 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 3.94 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:22])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.CN1CCOCC1.[N:30]([C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=1)=[C:31]=[O:32]>ClCCl>[F:41][C:40]([F:42])([F:43])[O:39][C:36]1[CH:35]=[CH:34][C:33]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][CH2:11][C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:22])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:32])=[CH:38][CH:37]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: C[C@@H]1NCCN(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
A solution of 0.050 g (0.16 mmol) of (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 13) and 0.053 ml (0.48 mmol) of 4-methylmorpholine in 1 ml of dichloromethane was treated at RT with 0.033 g (0.16 mmol) of 1-isocyanato-4-trifluoromethoxy-benzene (intermediate 14) in 1 ml of dichloromethane. After 1 h again 0.005 g of 0.033 g (0.16 mmol) of 1-isocyanato-4-trifluoromethoxy-benzene (intermediate 14) were added and after 30 min the reaction was extracted with aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield, after precipitation with dichloromethane/pentane, 0.077 g (93%) of the titled compound as white amorphous solid. MS: 513.23 (MH+).
Reaction SMILES: C[Al](C)C.[O:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[O:11][NH2:12].[CH2:13]([O:20][C@H:21]([C:39](OC)=[O:40])[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:34])[CH3:33])[S:27]([CH3:30])(=[O:29])=[O:28])=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:13]([O:20][C@H:21]([C:39](=[O:40])[NH:12][O:11][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][O:5]1)[C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]([CH2:31][CH:32]([CH3:33])[CH3:34])[S:27]([CH3:30])(=[O:28])=[O:29])=[O:24])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NOC1CCCCO1
Reactant: COC(=O)[C@@H](OCc1ccccc1)[C@@H](CC(C)C)C(=O)NN(CC(C)C)S(C)(=O)=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](OCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
0.530 ml of a 2M solution of trimethylaluminium in toluene was added to a solution of 0.124 g of O-(tetrahydro-2H-pyran-2(RS)-yl)-hydroxylamine in 5 ml of dry toluene at 0° C. under a nitrogen atmosphere. The mixture was stirred at 0° C. for 0.5 hours and then 0.335 g of 2(R)-[(S)-(benzyloxy)(methoxycarbonyl)methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide was added in one portion. The mixture was then left to warm to room temperature overnight. The mixture was diluted with ethyl acetate and washed in succession with 2M aqueous hydrochloric acid and 5% aqueous sodium hydrogen carbonate solution and then dried over anhydrous magnesium sulphate. The solvent was evaporated and the residue was triturated with hexane/diethyl ether (2:1) to give 0.119 g of 2(R)-[(S)-(benzyloxy)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]methyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH2:1]1[O:43][C:42]2[CH:41]=[CH:40][C:5]([CH2:6][N:7]([S:27]([C:30]3[C:35]([CH3:36])=[CH:34][C:33]([O:37][CH3:38])=[CH:32][C:31]=3[CH3:39])(=[O:29])=[O:28])[C@H:8]([CH2:12][NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])[C:9](O)=[O:10])=[CH:4][C:3]=2[O:2]1.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:44]([O:51][NH:52][C:9](=[O:10])[C@H:8]([N:7]([CH2:6][C:5]1[CH:40]=[CH:41][C:42]2[O:43][CH2:1][O:2][C:3]=2[CH:4]=1)[S:27]([C:30]1[C:31]([CH3:39])=[CH:32][C:33]([O:37][CH3:38])=[CH:34][C:35]=1[CH3:36])(=[O:28])=[O:29])[CH2:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26]1)=[O:15])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: NOCc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)O)c(C)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)NOCc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 53 %

Procedure:
To a mixture of 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionic acid (approximately 1.3 mmol), O-benzylhydroxylamine (0.6 ml, 3.9 mmol) and 1-hydroxybenzotriazole hydrate (199 mg, 1.3 mmol), and N-methylmorpholine (0.44 ml, 3.9 mmol) in anhydrous dimethylformamide (20 ml) was added 1-ethyl-3(3-dimethylamino)-propyl carbodiimide hydrochloride salt (375 mg, 1.95 mmol). The mixture was stirred overnight and then condensed on the roto-evaporator. The remainder was taken up in ethyl acetate (60 ml) and partitioned with an equal volume of 1.5% aqueous hydrochloric acid. The ethyl acetate phase was collected and washed consecutively with equal volumes of 5% sodium bicarbonate and then brine. The aqueous phases were back extracted with ethyl acetate (2×60 ml) and the organic layers combined, dried with magnesium sulfate, filtered and condensed. The residue was purified by preparative TLC (2% methanol-methylene chloride) providing N-benzyloxy-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionamide as a light yellow foamy solid (490 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([CH:12]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1N=[CH:19][NH:20]3)[CH2:13]C)=[N:7]2.O=C1CCC(=O)N1OC(=O)C(NC(OC(C)(C)C)=O)C[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.O=[C:61]1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC.C(O)(C(F)(F)F)=O.ClC1C2C=CNC=2N=CN=1.BrC1N=CN=C2C=1NC=N2>>[CH2:44]([O:43][CH2:13][CH:12]([C:6]1[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:4](=[O:31])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=1)[NH:15][C:16]1[C:17]2[CH:61]=[CH:19][NH:20][C:21]=2[N:22]=[CH:23][N:24]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)NC(COCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: Brc1ncnc2nc[nH]c12
Agent: Clc1ncnc2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2nc(C(COCc3ccccc3)Nc3ncnc4[nH]ccc34)n(-c3ccccc3)c(=O)c12

Procedure:
Compound 30 was prepared using the general procedure described above with respect to compound 14, but 3-benzyloxy-2-tert-butoxycarbonylaminopropionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, the alternate procedure (TFA deprotection) was used in step C, and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine was substituted for 6-bromopurine in step D. MS (ES): m/z 503 (M+H), 395. Compound 30is shown below.
Reaction SMILES: [Na].[NH:2]1[CH:6]=[C:5]([SH:7])[N:4]=[N:3]1.[S:8]1[CH:12]=C[CH:10]=[C:9]1CC(OCCl)=O.CN(C)C=[O:22]>O>[C:9]([S:8][CH2:12][S:7][C:5]1[N:4]=[N:3][NH:2][CH:6]=1)(=[O:22])[CH3:10]
Reactant: Sc1c[nH]nn1
Reactant: CN(C)C=O
Reactant: O=C(Cc1cccs1)OCCl
Agent: [Na]
Solvent: O
Product: CC(=O)SCSc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a suspension of 1,2,3-triazole-4-thiol sodium salt (38 g : 309 mMol.) in dimethylformamide (150 ml) at -20° C. is added dropwise chloromethyl thiolacetate (37.4 g : 300 mMol.) over 10 minutes, and the mixture is stirred at the same temperature for 30 minutes and at room temperature for 2 hours, diluted with water and extracted with ethyl acetate. The extract is washed with water, aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and concentrated under reduced pressure. The crystalline residue is washed with hexane, dried, and recrystallized from ether to give 4-acetylthiomethylthio-1,2,3-triazole (38.9 g). Yield: 69%, mp.88 to 89° C. .
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([O:17][CH3:16])[CH:19]=3)[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cccc(O)c1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: COc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 3-methoxy-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (159.4 mg, 42% for the final step); ES+-HRMS m/e calcd for C19H22N2O5 [M+H+] 359.1602, found 359.1600. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (br s, 2H), 1.31-1.80 (m, 7H), 1.87-2.09 (m, 1H), 2.09-2.25 (m, 1H), 3.78 (s, 3H), 5.31 (dd, J=11.0, 4.1 Hz, 1H), 5.79 (d, J=2.7 Hz, 1H), 6.85 (dd, J=7.8, 1.8 Hz, 1H), 6.89-6.96 (m, 2H), 7.42 (t, J=8.2 Hz, 1H), 8.08 (d, J=2.7 Hz, 1H), 13.03 (br s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1F.[O:18]1[C:22]2([CH2:26][CH2:25][NH:24][CH2:23]2)[O:21][CH2:20][CH2:19]1.C(OCC)(=O)C>C(#N)C.O>[F:7][C:8]1[CH:9]=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][C:13]=1[N:24]1[CH2:25][CH2:26][C:22]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:23]1
Reactant: C1CC2(CN1)OCCO2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Temperature: 75 °C

Procedure:
Potassium carbonate (6.9 g) was added to a mixture of 3,4-difluoronitrobenzene (8.0 g) and 1,4-dioxa-7-aza-spiro[4.4]nonane (12.9 g) in acetonitrile (34.6 mL) and the reaction mixture was heated for 2 h at 75° C. Ethyl acetate and water were added to the reaction mixture. The aqueous phase was extracted several times with ethyl acetate. The organic phases were combined, dried over sodium sulfate and the solvent was removed in vacuum. In this way the product was obtained with molecular weight 268.24 (C12H13FN2O4); MS (ESI): 269 (M+H+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].C(O)(=O)/C=C/C1C=CC(O)=C(O)C=1.P(Cl)(OCC)(OCC)=O.[CH3:42][N:43]([CH3:54])[CH2:44][CH2:45][NH:46][C@H:47]1[CH2:52][CH2:51][C@H:50]([CH3:53])[CH2:49][CH2:48]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:42][N:43]([CH3:54])[CH2:44][CH2:45][N:46]([C@H:47]1[CH2:48][CH2:49][C@H:50]([CH3:53])[CH2:51][CH2:52]1)[C:10](=[O:12])[CH:9]=[CH:8][C:7]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:19])[CH3:18])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: O=C(O)/C=C/c1ccc(O)c(O)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1OC(C)=O

Procedure:
Using 3.4 g of 3,4-diacetoxycinnamic acid derived from caffeic acid by the acetylation thereof, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3.0 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 0.68 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-diacetoxycinnamamide (a compound of the present invention) was obtained as pale yellow crystal, which had the following physiochemical properties:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:24][CH3:25])[C:20]=1[CH:21]([CH3:23])[CH3:22])[C:14]([O:16]C)=O.O.Cl>CCOCC>[CH3:25][O:24][C:19]1[CH:18]=[C:13]([C:14]([OH:16])([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=[C:11]([O:10][CH3:9])[C:20]=1[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)c1cc(OC)c(C(C)C)c(OC)c1
Reactant: BrCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1cc(C(O)(Cc2ccccc2)Cc2ccccc2)cc(OC)c1C(C)C
Temperature: 25 °C
Yield: 79 %

Procedure:
To Mg (0.252 g, 10.4 mmol) in dry ether (5 mL) was added benzylbromide (1 mL, 8.41 mL) in dry ether (3 mL) dropwise under reflux. After the addition was complete, the reaction mixture was further refluxed for 1 h. Methyl 3,5-dimethoxy-4-i-propylbenzoate (1.00 g, 4.20 mmol) in ether (15 mL) was added. After the ester completely disappeared, the reaction mixture was cooled to room temperature. Water (10 mL) was added followed by addition of 2N HCl (10 mL) to dissolve precipitate. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was dried over anhydrous Na2SO4. Evaporation of solvent followed by flash chromatography using ethyl acetate:hexane (1:9) afforded 2-(3,5-dimethoxy-4-i-propylphenyl)-1,3-diphenylpropan-2-ol (1.29 g, 79%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.28 (d, J=7.2 Hz, 6H), 3.08 (d, J=13.3 Hz, 2H), 3.35 (d, J=13.3 Hz, 2H), 3.6 (m, 1H), 3.95 (s, 6H), 6.44 (s, 2H), 6.9-7.5 (m, 10H).