Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:38])([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:38][C:2]([F:1])([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][CH:32]=[CH:31]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH2:20])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ccc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)cc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-(4-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl)ethylcarbamate (70 mg, 136 mol) in DCM (1 mL) and TFA (1 mL) was stirred for 30 min at 23° C. The solvents were then removed under reduced pressure and crude product purified by RP-HPLC eluting with water/ACN (0.1% TFA). The desired collected fractions were then concentrated under reduced pressure and the resulting residue dissolved in MeOH/DCM (5 mL). Solution was then stirred as a suspension with Si-Carbonated (300 mg; 0.2 mmol) for 30 min at 23° C. The solids were then removed by filtration, washed with MeOH (3×1 mL), and filtrate concentrated under reduced pressure. The product was isolated as a white fluffy solid. MS (ESI pos. ion) m/z: 417 (MH+). Calc'd exact mass for C23H18F2N6: 416.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][NH:16][CH3:17].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[CH3:15][N:16]([CH3:17])[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CNC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.5 %

Procedure:
To a solution of Boc-L-alanine (2.32 g, 12.26 mmol) in DCM (20 mL) was added dimethylamine hydrochloride (2 g, 24.5 mmol) and DIPEA (3.1 g, 24.53 mmol). The solution was kept at 0° C. for 10 min, then HOBt (3.31 g, 24.5 mmol) and EDCI (4.6 g, 24.5 mmol) were added. The mixture was stirred at room temperature for 10 h, and then poured into water (40 mL) and extracted with DCM (100 mL×3). The extracts was washed with brine (50 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (10-20% EtOAc in petroleum ether) to give Boc-L-alanine N,N-dimethyl amide as a colorless oil (1.1 g, 42%). 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 1 H), 5.51 (brs, 1H), 4.56-4.63 (m, 1H), 3.03 (s, 3H), 2.93 (s, 3 H), 1.39 (s, 9H), 1.26 (d, J=6.8, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38]([O:40][CH:41]([O:55][CH2:56][CH3:57])[CH2:42][NH:43][CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)[CH3:39].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([N:20]([CH3:37])[NH:21][C:22](=[O:36])[CH2:23][CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27])[C:17]([N:43]([CH2:42][CH:41]([O:40][CH2:38][CH3:39])[O:55][CH2:56][CH3:57])[CH2:44][C:45]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH:48]=[CH:47][CH:46]=2)=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(NC(=O)CCNC(=O)NCc1ccccc1)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CCOC(CNCc1cccc2ccccc12)OCC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(C)NC(=O)CCNC(=O)NCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.7 %

Procedure:
To a solution of (S)-3-(4-(benzyloxy)phenyl)-2-(2-(3-(3-benzylureido)propanoyl)-1-methylhydrazinyl)propanoic acid (Compound VII-1) 126 mg (0.25 mmol) in dichloromethane 1.5 ml, 2,2-diethoxy-N-(naphthalen-1-ylmethyl)ethanamine (Compound IV-2) 85 mg (0.31 mmol) and DMT-MM 173 mg (0.63 mmol) were added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with chloroform 50 ml and washed with water 50 ml twice and brine 50 ml twice and dried over magnesium sulfate and filtered. The mother solution was concentrated in vacuo and the residue was purified on silica gel column chromatography (Merck 60N spherical, neutral 10 ml elution by chloroform:methanol=100:0 to 90:10, each elution 50 ml) to give the desired product as pale yellow oil 85.0 mg (35.8%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[NH:17][C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8].Br[CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[CH2:7]([O:9][C:10]1[CH:23]=[CH:22][C:13](/[CH:14]=[C:15]2/[C:16](=[O:21])[N:17]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:20])[S:19]/2)=[CH:12][CH:11]=1)[CH3:8]
Reactant: CCOc1ccc(/C=C2\SC(=O)NC2=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(/C=C2\SC(=O)N(CCCNC(=O)OC(C)(C)C)C2=O)cc1
Reaction time: 0.33 h
Yield: 79.1 %

Procedure:
Potassium carbonate (350 mg, 2.53 mmol) was added to a solution of compound 2 (210 mg, 0.84 mmol) in 4 mL of anhydrous DMF at 0° C. After stirring of reaction mixture for 20 min, a solution of tert-butyl (3-bromopropyl)carbamate (200 mg, 0.84 mmol) in anhydrous DMF (3 mL) was added and then the reaction mixture was stirred at room temperature for 3 h. The reaction was quenched by adding water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% NH4Cl aqueous solution followed by water and dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% ethyl acetate in hexanes) to afford compound 21a (78.8%, 270 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.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.[NH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:54]=1[N:53]=[CH:52][CH:51]=[CH:50]2>C(Cl)Cl>[O:1]=[C:2]1[CH2:3][CH2:4][CH:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[CH:52][CH:51]=[CH:50]3)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: Nc1cccc2cccnc12
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: ClCCl
Product: O=C1CCC(C(=O)Nc2cccc3cccnc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a flask charged with 4-oxocyclohexane carboxylic acid (commercially available from Alfa Aesar, Ward Hill, Mass.) (2.000 mL, 14.07 mmol) were added DCM (56.3 mL), DIEA (5.16 mL, 29.5 mmol), HATU (5.35 g, 14.07 mmol) and 8-aminoquinoline (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2.130 g, 14.77 mmol) respectively. The resulting light brown suspension was stirred overnight at room temperature without much color change but complete dissolution of materials. LC-MS indicated product as the primary species. The solution was dried under reduced pressure and purified ramping with EtOAc in heptane from 0-50%, then isocratic at 50% which led to the system clogging up a bit due to precipitation of product. Product eluted following a less polar impurity and the system was flushed with DCM:MeOH:NH4OH (90:10:1) to elute the remainder of the product. Solid 4-oxo-N-(quinolin-8-yl)cyclohexanecarboxamide (1.900 g, 7.08 mmol, 50.3% yield) was obtained as a tan. 1H NMR (400 MHz, CDCl3) δ=10.02 (br. s., 1H), 8.83 (dd, J=1.7, 4.2 Hz, 1H), 8.78 (dd, J=2.2, 6.7 Hz, 1H), 8.20 (dd, J=1.7, 8.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.49 (dd, J=4.3, 8.3 Hz, 1H), 2.97 (tt, J=3.8, 10.5 Hz, 1H), 2.67-2.63 (m, 1H), 2.63-2.59 (m, 1H), 2.54-2.35 (m, 4H), 2.29-2.16 (m, 2H). m/z (ESI) 269.1 (M+H)+.
Reaction SMILES: [N+:1](C1C=C([N+]([O-])=O)C=CC=1O)([O-:3])=[O:2].[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=1[O:27][CH3:28])([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:22]=[C:21]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:20]=[C:19]([N+:1]([O-:3])=[O:2])[C:18]=1[O:27][CH3:28])([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
This product was then subjected to hydrolytic separation of the 2,4-dinitrophenol in accordance with the procedure described in Example 6 to afford 6.18 g (98.9% yield) that corresponds to 33.6% of total yield of the 2,4-dinitrophenol separated and 19.37 g 2,6-dinitro-4-tertbutylanisole (95.2% yield, calculated on the theoretical yield possible) contaminated with 3.88 g of the 2-nitro-4-tertbutylanisole. Subsequent crystallization from methyl alcohol (20 ml, cooled -5° C.) afforded 14.72 g of 99.4% pure 2,6-dinitro-4-tertbutylanisole with 57.5% total yield.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:48])([CH3:47])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:46])([C@@:13]3([CH3:45])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]1)[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[C:51]([C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56](B2OC(C)(C)C(C)(C)O2)=[CH:55][CH2:54]1)#[N:52]>>[C:51]([C:53]1([C:68]([O:70][CH3:71])=[O:69])[CH2:58][CH2:57][C:56]([C:7]2[C:8]([CH3:47])([CH3:48])[C@H:9]3[C@:22]([CH3:25])([CH2:23][CH:24]=2)[C@@H:21]2[C@:12]([CH3:46])([C@@:13]4([CH3:45])[C@H:18]([CH2:19][CH2:20]2)[C@H:17]2[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]2([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([S:41]([CH3:44])(=[O:43])=[O:42])[CH2:37][CH2:36]2)[CH2:15][CH2:14]4)[CH2:11][CH2:10]3)=[CH:55][CH2:54]1)#[N:52]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: COC(=O)C1(C#N)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C#N)(C(=O)OC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 61 %

Procedure:
The title compound was prepared following the procedure described in general procedure Step 5, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate and methyl 1-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate as reactants. The product was isolated as a mixture of diasteromers (solid, 61% yield). MS: m/e 762.6 (M+H)+, 3.01 min (method 4). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.34 (d, J=2.0 Hz, 1H), 5.28-5.22 (m, 1H), 4.71 (d, J=2.0 Hz, 1H), 4.60-4.57 (m, 1H), 3.85 (s, 3H), 3.17-3.06 (m, 3H), 2.87-2.78 (m, 2H), 2.84 (s. 3H), 2.74-2.40 (m, 10H), 2.33-0.78 (m, 27H), 1.69 (s, 3H), 1.07 (s, 3H), 1.01-0.93 (m, 6H), 0.96 (s, 3H), 0.85 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([Si:8]([C:13]#[CH:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH3:7].B(F)(F)F.CCOCC.[CH2:24]([O:31][CH2:32][C@@H:33]1[O:35][CH2:34]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH4+].[Cl-]>C1COCC1>[CH2:24]([O:31][CH2:32][C@H:33]([OH:35])[CH2:34][C:14]#[C:13][Si:8]([CH2:11][CH3:12])([CH2:9][CH3:10])[CH2:6][CH3:7])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C#C[Si](CC)(CC)CC
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[Si](C#CC[C@@H](O)COCc1ccccc1)(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
Butyllithium (48 ml, 1.6 M) was added to triethylsilylacetylene (10.7 g, 76.4 mmol) in THF (90 ml) at -78° C. over 20 min. After 10 min BF3.OEt2 (10 ml, 82 mmol) was added, then after another 10 min (-)-benzyl-(R)-glycidyl ether (8.4 g, 51 mmol) in THF (20 ml) was added over 10 min. The mixture was stirred at -78° C. for 1 h then at 0° C. for 20 min. Saturated NH4Cl was added and the mixture extracted with EtOAc (×3). The combined organic layers were washed with H2O and brine, dried, evaporated, and purified by chromatography to give (R)-5-benzyloxy-4-hydroxy-1-triethylsilyl-1-pentyne (9.4 g, 61%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]([O-:17])=[O:16])=[CH:9][CH:8]=2)[N:3]=1.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccc(NCC(=O)[O-])cc2)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc(-c2ccc(NCC(=O)O)cc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.5 %

Procedure:
Into a 250 ml round-bottomed flask 55.0 g (19.1 millimoles) of N-[4-(5-methyl-1,2,4-oxadiazol-3-yl)-phenyl]-glycinate (13, R is methyl) and 100 ml of a 5 vol % sodium hydroxide solution (125 millimoles) are weighed in. The suspension obtained is stirred at room temperature for 16-20 hours. The solution obtained is cooled and the pH is adjusted to 5 with a 1:1 diluted mixture of concentrated hydrochloric acid and water. The precipitate is filtered, washed with water and dried in vacuo to constant weight. Thus 4.30 g of the title compound are obtained (97%). Mp.: 178-181° C.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][Mg]Br>C1COCC1.C(OCC)C>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)([OH:22])[CH3:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)c1cc2ccccc2s1
Temperature: -30 °C

Procedure:
To a stirring solution consisting of (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (intermediate 4a prepared in Example 2, Step A) in THF (0.2 M) at −30° C. under a nitrogen atmosphere is slowly added a solution consisting of methylmagnesium bromide in diethyl ether (3 M, 1.5 molar equivalents). The reaction mixture is stirred at −30° C. until the reaction is complete as judged by TLC. Upon completion, the reaction mixture is warmed to 0° C. and is quenched with water and extracted into ethyl acetate. The layers are separated and the aqueous phase is extracted with a fresh portion of ethyl acetate. The organic layers are combined and dried over magnesium sulfate. The solvents are evaporated and the crude material is purified on regular silica gel eluted with an ethyl acetate-hexanes solvent system to afford the title intermediate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH3:30])[C:31]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11])=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H]1Cc2ccccc2N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
There are introduced into a reactor, with stirring, 2.13 kg of methyl(2S)-2,3-dihydroindole-2-carboxylate, 1 kg of triethylamine, 30 litres of tetrahydrofuran and then, after 10 minutes' stirring at room temperature, 1.9 kg of N-[tert-butyloxycarbonyl]-(S)-alanine and 2 kg of dicyclohexylcarbodiimide. The heterogeneous mixture is then stirred at room temperature for 6 hours, and is subsequently cooled to 0° C. and filtered.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:15]=[CH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: N
Reactant: COC(=O)CC(=O)Nc1ccc(C=Cc2cccc(F)c2)cc1
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(C=Cc2cccc(F)c2)cc1
Yield: 68 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=68%. Colorless solid. MS: m/e=299.2 (M++H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([N:28]1[C:32]([OH:33])=[CH:31][CH:30]=[N:29]1)[CH3:27].C1(N=C=NC2CCCCC2)CCCCC1>C(O)(CC)(C)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([C:31]1[CH:30]=[N:29][N:28]([CH2:26][CH3:27])[C:32]=1[OH:33])=[O:6]
Reactant: CCn1nccc1O
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)(C)O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(OCCOC)c2Cl)c1O

Procedure:
1.2 g of the crude product of 2-chloro-4-methanesulfonyl-3-(2-methoxy)ethoxybenzoic acid, 0.3 g of potassium carbonate, 0.45 g of 1-ethyl-5-hydroxypyrazole and 0.77 g of N,N'-dicyclohexyl carbodiimide were put into 40 ml of t-amyl alcohol, and the mixture was stirred under heating at a temperature of from 80° to 90° C. for from 4 to 5 hours. The solvent was distilled off, and a dilute potassium carbonate aqueous solution was added to the residue. The mixture was washed with chloroform. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain a crude product of the above identified compound. The crude product was recrystallized from ethanol to obtain 0.3 g of the desired product. Melting point: 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)cc1Cl
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Methyl 2-chloro-4-hydroxybenzoate (Acros Organics; 0.2 g, 1.072 mmol) was stirred with 2-bromopropane (0.201 ml, 2.144 mmol) and potassium carbonate (296 mg, 2.144 mmol) in DMF (2 ml) at 100° C. for 1.5 hr. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by Mass-Directed Auto-Preparative HPLC (formic acid modifier) to give the title compound as a yellow oil (150 mg).
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].Cl>C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 18 h

Procedure:
A solution of NaOH (144.8 g, 3.42 mol; assay=94.5%), water (2573 ml), ethanol (2187 ml) and Trandolapril (680 g, 1.58 mol; assay=99.81%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 18 hours. After an in process control showed an almost complete saponification (by HPLC), the pH of the clear solution was adjusted to 3.8 by addition of 2N aqueous hydrochloric acid at a temperature ranging from about 20° C. to about 25° C. (The solution was seeded according to the general seeding procedure, see Example 2). The suspension was stirred at a temperature ranging from about 20 to about 25° C. for 5.5 hours, and then filtered off, and the wet product was washed with water (2149 ml) and ethanol (2198 ml). Then, a suspension of the wet product in ethanol (6046 ml) was stirred at a temperature ranging from about 38° C. to about 43° C. for 14 hours, and then at a temperature ranging from about 20° C. to about 25° C. for 2 hours. After filtration, the wet product was washed with ethanol (2224 ml) and dried in vacuo (<1 mbar) at 40° C. until the ethanol content was <0.5% (4 days) to give Trandolaprilat as crystalline Form E (yield: 582 g, 1.44 mol, 91.3%; assay (NaOH)=99.74%; HPLC purity: 99.33%, Trandolaprilat diketopiperazine: 0.52%; water content: 0.54%, ethanol content: 955 ppm, chloride content=not detected).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)[N:37]=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]=3)[S:13][C:6]=12.C(C(O)=O)(F)(F)F>>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:35](=[O:47])[N:36]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)[N:37]=[CH:38][CH:39]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH:15]=3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A single-neck, round-bottomed flask was charged with tert-butyl 4-(7-(2-fluoro -4-(2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (27.3 mg, 0.0415 mmol) and CF3CO2H (5 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (four hours). Then the solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (16.7 mg, 72.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 558 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.42 (m, 2H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.60 (m, 2H), 7.38 (m, 2H), 7.24 (m, 3H), 6.48 (d, 1H), 6.40 (s, 1H), 3.59 (m, 2H), 3.15 (m, 2H), 2.58 (m, 2H).