Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Yield: 55 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methyl-1H-pyrazol-4-ylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (70 mg, 55%) which was obtained as a yellow oil after purification by chromatography (silica, heptane:ethyl acetate 9:1 to 1:1). MS: m/e=370.2 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:27])[C:9]([C@@H:10]([CH3:25])[CH2:11]2)=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]1.[CH2:28]([O:30][CH2:31][CH2:32][C:33](Cl)=[O:34])[CH3:29]>>[CH2:28]([O:30][CH2:31][CH2:32][C:33]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:27])[C:9](=[CH:8][C:7](=[O:26])[CH:6]=[CH:5]2)[C@@H:10]([CH3:25])[CH2:11]3)[CH2:14][CH2:15]1)=[O:34])[CH3:29]
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: CCOCCC(=O)Cl
Product: CCOCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
15.0 g of 11β,17,21-trihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted analogously to Example 4(a) with 3-ethoxypropionic acid chloride, worked up, and purified, thus isolating 13.6 g of 21-(3-ethoxypropionyloxy)-11β,17-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 186° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77-11.78 (bs, 1H), 8.39-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.60-7.65 (m, 4H), 7.06-7.20 (m, 3H), 3.76 (s, 2H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: Cl.C[O:3][C:4]([C:8]1[S:9][C:10]([C:13]2([OH:22])[CH2:18][CH2:17][CH2:16][N:15]3[CH:19]=[N:20][CH:21]=[C:14]23)=[CH:11][N:12]=1)(OC)[CH3:5].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[OH:22][C:13]1([C:10]2[S:9][C:8]([C:4](=[O:3])[CH3:5])=[N:12][CH:11]=2)[CH2:18][CH2:17][CH2:16][N:15]2[CH:19]=[N:20][CH:21]=[C:14]12
Reactant: COC(C)(OC)c1ncc(C2(O)CCCn3cncc32)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ncc(C2(O)CCCn3cncc32)s1
Reaction time: 2 h

Procedure:
5 ml of conc. HCl are added dropwise to a solution of 0.31 g of 8-[2-(1,1-dimethoxyethyl)thiazol-5-yl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol and 20 ml of 1:1 acetone/water at room temperature, and the mixture is stirred for 2 hours. The reaction mixture is evaporated—the residue is mixed with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3×). The combined organic phases are dried with sodium sulphate and evaporated. The title compound is identified from the residue by flash chromatography (SiO2 60F) on the basis of the Rf.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)[CH3:2]>Cl>[CH2:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCc1nnc(-c2ccc(OC)cc2)n1-c1ccc(N)cc1
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A solution of 23 g of stannous chloride in 20 ml of concentrated hydrochloric acid was added all at once to a solution of 10 g of 3-ethyl-5-(4-methoxyphenyl)-4-(4-nitrophenyl)-4H-1,2,4-triazole in 50 ml of concentrated hydrochloric acid and the mixture was vigorously stirred for 2 hours and was filtered. The recovered product was washed with N hydrochloric acid and was added to aqueous 5N sodium hydroxide solution. The mixture was stirred for 2 hours and was filtered and the white crystals were washed and dried at 110° C. under reduced pressure. The 12.5 g of crystals were dissolved in boiling toluene and the mixture was filtered. The filtrate was iced for 16 hours and was vacuum filtered. The product was dried to obtain 3.8 g of 4-[3-ethyl-5-(4-methoxyphenyl)-4H-1,2,4-triazol-4-yl]-benzeneamine in the form of crystals melting at 216° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(COC)OC>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:10]=[CH:11][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:13][CH:14]=2)=[CH:31][N:32]=1
Reactant: Nc1ncc(Br)cn1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(-c4cnc(N)nc4)cc3)(CC1)CO2
Temperature: 25 °C
Yield: 105 %

Procedure:
To a reaction vial containing methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (200 mg, 0.52 mmol), 5-bromopyrimidin-2-amine (108 mg, 0.62 mmol) and K3PO4 (132 mg, 0.62 mmol) was added dimethoxyethane (4.8 ml). The mixture was stirred at room temperature and degassed after the addition of EtOH (1.6 ml) and water (0.64 ml). PdCl2(dppf) DCM adduct (21 mg, 0.03 mmol) was added and the mixture was heated to 8° C. in an oil bath for 3 hours. The reaction mixture was then concentrated to dryness and taken up in DCM. The slurry was dried over sodium sulfate and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography to afford the title compound (193 mg, 84% yield). LC/MS, ESI-MS(+): 354.3, RT: 1.06 (Condition E).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH:7]1[CH3:16])=[O:5])C.[OH-].[K+].Cl.O>CO>[CH3:16][C@H:7]1[C@@H:6]([C:4]([OH:5])=[O:3])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8]1
Reactant: CCOC(=O)C1CCC2(CC1C)OCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H]1CC2(CC[C@@H]1C(=O)O)OCCO2
Yield: 95 %

Procedure:
Dissolve 7-methyl-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (R. R. Crenshaw, etc., J. Med. Chem., 1973, 16(7), 813-823) (14.09 g, 61.7 mmol) in MeOH (300 mL) and add 2M KOH (60 mL, 120 mmol, 2M in H2O). Stir the reaction for overnight at room temperature, then add 1N HCl until pH=3. Remove MeOH under reduced pressure and add water (200 mL). Extract the aqueous layer with ethyl acetate (3×400 mL). Combine the organic layers and dry with Na2SO4, filter and concentrate to give 11.74 g (95%) of the crude title compound as a white solid
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([O:27]C)=[O:26])=[CH:7][C@H:6]1[O:29][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([NH:4][C@H:5]1[C@H:10]([C:11](=[O:24])[NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8]([C:25]([OH:27])=[O:26])=[CH:7][C@H:6]1[OH:29])(=[O:3])[CH3:2]
Reactant: COC(=O)C1=C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](NC(C)=O)[C@H](C(=O)NCCCCCc2ccccc2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)N[C@@H]1[C@H](O)C=C(C(=O)O)O[C@H]1C(=O)NCCCCCc1ccccc1
Yield: 93.6 %

Procedure:
To a stirred solution of (4R,5S,6R)-5-acetylamino-4-(tert-butyldiphenylsilanyloxy)-6-(phenethylpropylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid, methyl ester (7 g) in tetrahydrofuran (70 ml) was added tetra-n-butylammonium fluoride (12 ml of a 1M solution in tetrahydrofuran). After 4 hours at 23° C. the solvent was removed in vacuo and the residue was partitioned between brine and ethyl acetate. The organic extracts were dried over anhydrous sodium sulphate and the solvent was removed in vacuo to give an oil. This was chromatographed over silica (Merck 9385, 700 ml) using medium pressure (ca 4 psi) and dichloromethane/methanol (95:5 v/v) as eluant. The required fractions were combined and the solvent removed in vacuo to give the title compound as a pale yellow foam (3.98 g). 1H NMR (250MHz, CDCl3, rotamers) 7.3 (5H,m), 6.2 (1H, 2×d, J=4Hz), 5.1+4.9 (1H,2×d, J=6Hz), 4.6+4.5 (1H, 2×m), 4.4--4.2 (1H,2× m), 3.8 (3H, 2×s), 3.7--3.3 (4H, m), 3.0+2.8 (2H, 2×m), 2.0 (3H, 2×s), 1.8--1.3 (2H, m), 0.9 (3H, m); Mass spec. (low resolution) MH+ =405.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30]C)=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:37])[C@H:13]([CH2:14][S:15]2(=[O:33])=[O:32])[C@:12]2([CH3:34])[C@H:7]([C:8]([CH3:36])([CH3:35])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.O[Li].O>CO.O>[OH:1][C:2]1[CH:19]=[C:18]([C:20]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]2)=[O:21])[CH:17]=[C:16]2[C:3]=1[C@@:4]1([CH3:37])[C@H:13]([CH2:14][S:15]2(=[O:33])=[O:32])[C@:12]2([CH3:34])[C@H:7]([C:8]([CH3:36])([CH3:35])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCN(C(=O)c2cc(O)c3c(c2)S(=O)(=O)C[C@@H]2[C@@]4(C)CCCC(C)(C)[C@@H]4CC[C@@]32C)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(C(=O)N5CCC(C(=O)O)CC5)cc(O)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A mixture of methyl 1-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]carbonyl}piperidine-4-carboxylate (97) (0.10 g, 0.18 mmol) and LiOH.H2O (0.10 g, 2.4 mmol) in MeOH (10 mL) and water (2.0 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and acidified with 1 M HCl. The resulting solid was collected by filtration to give 1-{[(1R,10R,11S,16S)-3-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-5-yl]carbonyl}piperidine-4-carboxylic acid (98) (0.06 g, 63%) as a white solid. 1H NMR (CD3OD): δ 7.29 (d, 1H), 6.97 (d, 1H), 4.43 (m, 1H), 3.70 (m, 1H), 3.58 (m, 1H), 3.36 (m, 2H), 3.26-2.96 (m, 4H), 2.62 (m, 1H), 2.24 9d, 1H), 2.10-1.16 (m, 13H), 1.09-0.99 (m, 5H), 0.90 (s, 3H), 0.88 (s, 3H). MS m/z 516 (C28H39NO6S−H+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+]>O>[C:1]([C:29]1[C:28]([CH3:31])=[CH:27][C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[C:19](=[CH:24]\[O:25][CH3:26])/[C:20]([O:22][CH3:23])=[O:21])=[C:9]([CH3:8])[CH:30]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(C)=O)cc1C
Yield: 81 %

Procedure:
Acetic anhydride (26 mL, 5 eq) was stirred together with methane sulfonyl (18 mL, 5 eq) at room temperature for 30 min and then combined with 18.0 g (55.16 mmol) of (E)-methyl 2-(2-((2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in step 1 at room temperature for an additional one hour. After completion of the reaction, the reaction mixture was dropwise added to water (500 mL), adjusted to pH 7 with 25%-NaOH and extracted twice with 250 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and filtered after which the solvent was removed by concentration in a vacuum. Crystallization in 100 mL of isopropyl ether (IPE) afforded 16.5 g of (E)-methyl 2-(2-((4-acetyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate in 81% yield as an ivory solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][N:19]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[NH2:30][NH2:31]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:30][NH:31][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:22]([CH3:23])[N:21]=[CH:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: CO
Product: Cn1ncnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A 100 mL round-bottom flask equipped with a thermometer and magnetic stirrer was charged with ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (1.72 g, 4.4 mmol), methanol (15 mL), and NH2NH2 (4 mL, 85%). The mixture was stirred at 25° C. for 5 hr. The reaction was monitored by HPLC for completion. The mixture was evaporated under reduced pressure and methanol was added to make slurry. The suspension was filtered. The obtained solid was washed with 20 mL of methanol, and was dried to afford the title compound (1.4 g, yield 90%). LC-MS (ESI) m/z: 363 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.65 (s, 3H), 4.93-4.97 (m, 2H), 7.12-7.19 (m, 3H), 7.39-7.43 (m, 2H), 7.47-7.50 (m, 2H), 7.58-7.60 (m, 1H), 7.79 (s, 1H), 12.22 (s, 3H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=1[O:32][CH3:33].O.ON1C2C=CC=CC=2N=N1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]2)=[O:29])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(C(=O)O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.26 g) and diisopropylethylamine (2.05 mL) were added to a room temperature solution of 4-chloro-3-methoxybenzoic acid (2.00 g) and 1-hydroxybenzotriazole hydrate (1.81 g) in dichloromethane (53 mL). After the reaction was stirred for five minutes, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (2.53 g) was added and the mixture was stirred overnight. The reaction was then partitioned between 1 N hydrochloric acid and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated and purified by column chromatography on silica gel (dichloromethane:methanol=19:1). The resulting residue was triturated in diethyl ether and the solids were collected by filtration to obtain the title compound (3.56 g) having the following physical data. 1H NMR (DMSO-d6): δ 8.60 (t, J=5.7 Hz, 1H), 7.61-7.39 (m, 3H), 3.91 (m, 5H), 3.15 (t, J=6.0 Hz, 2H), 2.81-2.62 (m, 2H), 1.72-1.51 (m, 3H), 1.39 (s, 9H), 1.12-0.92 (m, 2H)+;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][NH:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:14].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNCC(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][N:27]([CH:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:11])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1N=C=O
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: COc1ccccc1NC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 80 an appropriate amount of 2-methoxyphenylisocyanate was substituted for ethyl isocyanato acetate and an appropriate amount of the product of Example 4 was substituted for the product of Example 70 and the general procedure of Example 80 was followed the title compound was obtained. Total yield, 1.56 g (76%).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][CH:13]([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:12][CH:13]([CH3:32])[C:14]([O:16][CH:17]([O:21][C:22]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)C(=O)OC(OC(=O)ON1C(=O)CCC1=O)C(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C(=O)OC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)C(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]-2-methylpropyl 2-methylpropanoate (603 mg, 2.0 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 44 (486 mg, 71% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ =0.82-0.94 (br. m, 8H), 1.06 (d, J=6.8 Hz, 3H), 1.08 (d, J=7.2 Hz, 3H), 1.16-1.38 (br. m, 3H), 1.64-1.73 (br. m, 2H), 1.82-1.92 (br. m, 3H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.52 (hept., J=6.8 Hz, 1H), 2.74-2.87 (br. m, 2H), 6.42 (d, J=5.2 Hz, 1H), 7.40 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 366.08 (M+Na)+; 342.04 (M−H)−.
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[N:11]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:25])[CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:11]1[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][C:10]1=[O:25])[CH3:24]
Reactant: CCOC(=O)CN1C(=O)CN(C(=O)OC(C)(C)C)Cc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CN1C(=O)CNCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 1-ethoxycarbonylmethyl-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (125 mg, 0.36 mmol) in dry DCM (5 mL) was added trifluoroacetic acid (1.08 mL, 3 mL/mmol). The reaction mixture was stirred at r.t. for one hour. After completion of the reaction, as confirmed by TLC, excess of trifluoroacetic acid and DCM were evaporated in vacuo to afford trifluoroacetic acid salt of (2-oxo-2,3,4,5-tetrahydro-benzo[e][1,4]diazepin-1-yl)-acetic acid ethyl ester (119 mg, 92%) as a gummy solid which was used as such without any further purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28](O)=[O:29])=[N:10]1.Cl.CN(C)CCCN=C=NCC.FC1C(O)=C(F)C(F)=C(F)C=1F.[NH2:57][CH2:58][C:59]1[CH:67]=[CH:66][C:62]([C:63]([OH:65])=[O:64])=[CH:61][CH:60]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][O:26][C:27]([CH3:32])([CH3:31])[C:28]([NH:57][CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:63]([OH:65])=[O:64])=[CH:66][CH:67]=2)=[O:29])=[N:10]1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: Cc1c(COC(C)(C)C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(COC(C)(C)C(=O)NCc2ccc(C(=O)O)cc2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 600 mg of 2-[1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazol-3-ylmethoxy]-2-methyl-propionic acid in 9 ml of DMF, 283 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), 271 mg of pentafluorophenol and 300 mg of NEM was added and the reaction mixture was stirred for 3 h at room temperature. Then, 278 mg of 4-Aminomethyl-benzoic acid and 424 mg of NEM in 10 ml of DMF were added. After 16 h the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 204 mg.
Reaction SMILES: CC[O-].[Na+].[Na].[SH:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1.Cl[CH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[C:28]#[N:29]>C(O)C>[C:28]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:22]1[CH2:21][S:6][C:7]1[CH:8]=[C:9]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)#[N:29]
Reactant: N#C[C@@H]1CCCC[C@H]1CCl
Reactant: CCOC(=O)C(C)c1cccc(S)c1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)c1cccc(SCC2CCCCC2C#N)c1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
Sodium ethylate prepared from sodium (0.23 g) and ethanol (10 ml) was added to ethyl 2-(3-mercaptophenyl)propionate (2.10 g) and the mixture was stirred for a while. Thereto was added trans-2-(chloromethyl)cyclohexanenitrile (1.58 g) and the resulting mixture was refluxed for 5 hours in an oil bath maintained at 100° C. The reaction mixture was evaporated to dryness under reduced pressure and to the residue was added toluene. After removal of the insoluble material by filtration, the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel, using chloroform as an eluent, to give ethyl 2-[3-(2-cyanocyclohexylmethylthio)phenyl]propionate (2.6 g) as an oil. IRνmaxfilm cm-1 : 2230 (C≡N), 1720 (C=O). MS m/e: 331 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.ICI.[Sm].O1CC[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([OH:7])[CH2:18][CH2:17]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [Sm]
Solvent: ICI
Product: OC1(c2cccc(Cl)c2)CC1
Temperature: -10 °C

Procedure:
A solution of methyl 3-chlorobenzoate (0.27 g, 1.58 mmol) and diiodomethane) in anhydrous tetrahydrofuran was added slowly to a vigorously stirred and heated (50° C.) slurry of samarium powder (1.0 g, 6.65 mmol) in tetrahydrofuran over 1.5 hours. After complete addition, the reaction mixture was stirred for 1 hour, than cooled (−10° C.), quenched with 1 N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) afford 100 mg of 1-(3-chlorophenyl)cyclopropanol.