Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([C:9](Cl)=[C:10]([CH3:13])[CH:11]=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[H][H]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH3:13])[CH:11]=[O:12])=[CH:15][CH:16]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: CC(C=O)=C(Cl)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Yield: 88 %

Procedure:
4-tert-Butyl-β-chloro-α-methylcinnamaldehyde (71 g), 1.0 g of 5% Pd/C, 40 g of 30% sodium hydroxide solution, 40 g of water and 32 g of methanol were placed in a Parr apparatus and hydrogenated at 20-50 psi until the theoretical amount of hydrogen had been absorbed (about 31/2 hrs.). The solution was filtered and the aqueous phase extracted with 100 g of ethylene dichloride. The solution was distilled to yield 53.9 g (76%) of the desired product, bp 100° (1.0 mm).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-trifluoromethyl-pyridine following a procedure analogous to that described in Example 19. LC (method 5): tR=2.18 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]2[CH2:16][O:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:26]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH2:19]([C:26]1([OH:32])[CH2:31][CH2:30][N:29]([CH2:16][CH:14]([OH:15])[CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:18])[CH3:17])=[CH:8][CH:9]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC2CO2)cc1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Yield: 89.1 %

Procedure:
(RS)-tert-Butyl-dimethyl-(4-oxiranylmethyl-phenoxy)-silane (0.62 g, 2.34 mmol) was dissolved in MeOH (8 ml) and stirred overnight at room temperature in the presence of 4-benzyl-4-hydroxy-piperidine (0.9 g, 4.68 mmol). The reaction mixture was concentrated and the residue was chromatographed over silica gel (hexane-ethylacetate 1:1, then CH2Cl2 --MeOH 19:1) to provide (RS)-4-Benzyl-1-{3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-2-hydroxy-propyl}-piperidin-4-ol (0.95 g, 90%) as a yellow oil, MS: m/e=456.5 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[OH-:25].[Na+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:33]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:33])=[O:25])=[CH:16][C:15]=2[S:21](=[O:23])(=[O:22])[NH2:24])(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cc1ccc(NS(=O)(=O)CCc2ccc(Br)cc2)c(S(N)(=O)=O)c1
Reactant: [OH-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Temperature: 70 °C
Yield: 69 %

Procedure:
To a suspension of 2-[2-(4-bromo-phenyl)-ethanesulfonylamino]-5-methyl-benzenesulfonamide (0.3 g, 0.69 mmol) in water (12 mL) was added 2.5 M sodium hydroxide until a clear solution was obtained (˜12 mL). Potassium permanganate (0.55 g, 3.46 mmol) was added and the resulting reaction mixture was heated at 70° C. for 3 hours. The hot solution was filtered through a pad of Celite and the solids were washed with water. Solid sodium bisulfate was added to the filtrate until the pink color disappeared. The aqueous solution was treated with charcoal, filtered, and the pH was adjusted to pH˜1 using 6 M hydrochloric acid. The formed precipitate was collected by filtration, washed with water, and dried to give 0.22 g (69% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:32])=[O:33])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CN1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CN1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-methylpiperazine. MS (ESI): mass calcd. for C21H22FN5O2S, 427.15; m/z found, 428.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.37 (m, 1H), 8.23 (d, J=1.4, 1H), 8.16-8.12 (m, 1H), 8.02-7.96 (m, 1H), 7.78-7.73 (m, 1H), 7.68-7.62 (m, 1H), 7.48-7.45 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.61-3.33 (m, 4H), 3.01-2.70 (m, 7H).
Reaction SMILES: Cl.Cl.[F:3][C@H:4]1[C:8]2[N:9]=[CH:10][N:11]=[C:12]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[C@H:6]([CH3:19])[CH2:5]1.C(OC([N:27]([CH2:40][CH:41]1[CH2:43][CH2:42]1)[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=O)(C)(C)C.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C@@H:29]([CH2:28][NH:27][CH2:40][CH:41]2[CH2:43][CH2:42]2)[C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:12]3[C:7]4[C@H:6]([CH3:19])[CH2:5][C@@H:4]([F:3])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:18][CH2:17]2)=[O:31])=[CH:38][CH:37]=1
Reactant: C[C@@H]1C[C@@H](F)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](C(=O)O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](F)c2ncnc(N3CCN(C(=O)[C@H](CNCC4CC4)c4ccc(Cl)cc4)CC3)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5R,7R)-7-Fluoro-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.535 g, 1.730 mmol) and (S)-3-(tert-butoxycarbonyl(cyclopropylmethyl)amino)-2-(4-chlorophenyl)propanoic acid (0.6122 g, 1.730 mmol) were combined in methylene chloride (15 mL) and treated with diisopropylethylamine (0.9041 ml, 5.191 mmol). HBTU (0.6579 g, 1.730 mmol) was then added. The reaction was stirred at ambient temperature for 16 hours. ESI MS looked excellent for desired product. The reaction was quenched with 10% Na2CO3, diluted with methylene chloride and separated. The aqueous portion was washed with methylene chloride (2×), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The material was applied to a 40 mm samplet and air-dried. This was placed on top of a column (Biotage 40S) and eluted with 3:2 hexane/EtOAc. The major spot was collected to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-fluoro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(cyclopropylmethyl)carbamate as a white solid (955 mg, 96%). LC/MS (APCI+) m/z 571.9 [M+H]+
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:11])[CH2:24][CH2:25]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]([N:18]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH:19]1[C:27](=[O:41])[NH:28][CH:29]([CH:33]([C:35](=[O:40])[NH:36][CH:37]1[CH2:39][CH2:38]1)[OH:34])[CH2:30][CH2:31][CH3:32])=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[CH:37]1([NH:36][C:35]([CH:33]([OH:34])[CH:29]([NH:28][C:27]([CH:19]2[CH2:20][CH:21]3[CH:26]([CH2:25][CH2:24][CH2:23][CH2:22]3)[N:18]2[C:16](=[O:17])[CH:11]([NH2:10])[C:12]([CH3:14])([CH3:13])[CH3:15])=[O:41])[CH2:30][CH2:31][CH3:32])=[O:40])[CH2:38][CH2:39]1
Reactant: [H][H]
Reactant: CCCC(NC(=O)C1CC2CCCCC2N1C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C)C(O)C(=O)NC1CC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(NC(=O)C1CC2CCCCC2N1C(=O)C(N)C(C)(C)C)C(O)C(=O)NC1CC1
Yield: 10.9 %

Procedure:
Amide 93 (10.10 g, 1.0 eq) in EtOH (10 mL) was treated with 10% Pd/C (100 mg) and hydrogen gas was bubbled into the black suspension until starting material was consumed (monitored by TLC). Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 852 mg (100% yield) of 1-(2-amino-3,3-dimethyl-butyryl)-octahydro-indole-2-carboxylic acid [1-(cyclopropylcarbamoyl-hydroxy-methyl)-butyl]-amide 94 as a white solid with consistent NMR data. 1H NMR (CDCl3) δ 4.40 (m, 1H), 4.20 (m, 1H), 4.10 (d, 1H), 3.95 (m, 1H), 2.70 (m, 1H), 2.40 (m, 2H), 2.0 (m, 2H), 1.60-1.80 (m, 6H), 1.50 (m, 2H), 1.30 (m, 3H), 1.20 (m, 1H), 1.00 (s, 9H), 0.90 (m, 3H), 0.75 (m, 2H), 0.55 (m, 2H)ppm.
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CC(=O)CC.C(OC(=O)C)(=O)C.[O-2].[Mg+2]>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-acetoacetyl-L-aspartic acid, 21.7 parts, was mixed with 25 parts by volume of 2-butanone and 10.8 parts acetic anhydride. A solution of 0.056 parts magnesium oxide in 2.0 parts by volume of glacial acetic acid was added and the mixture was stirred at room temperature for 90 minutes. The solid was collected on a filter under nitrogen, rinsed with 2-butanone, and dried at 0.1 mm to afford 17.3 parts N-aceto-acetyl-L-aspartic anhydride.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH2:5][CH:6]([CH3:9])[CH2:7][CH3:8].O=S(Cl)[Cl:12]>>[Cl-:12].[Cl:12][CH2:2][CH2:3][NH2+:4][CH2:5][CH:6]([CH3:9])[CH2:7][CH3:8]
Reactant: CCC(C)CNCCO
Reactant: O=S(Cl)Cl
Product: CCC(C)C[NH2+]CCCl
Product: [Cl-]

Procedure:
N-(2-Hydroxyethyl)-N-(2-methylbutyl)amine was reacted with SOCl2 according to Method B7a to give N-(2-chloroethyl)-N-(2-methylbutyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give to give 2-(2-methyl-4-nitrophenylimino)-3-(2-methyl-1-butyl)-1,3-thiazolidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20][CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:21][S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CSc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccccc1-c1ccc2[nH]ccc2c1
Reaction time: 0.33 h
Yield: 52.2 %

Procedure:
A solution of 5-indoleboronic acid (2.0 g, 12 mmol) and 2-bromothioanisole (1.6 mL, 12 mmol) in a mixture of ethylene glycol dimethyl ether (20 mL) and aqueous sodium carbonate (10 mL) was deoxygenated by a rapid stream of nitrogen applied to the system for 20 min, then treated with Pd(0) at once. The reaction was refluxed for 18 h, cooled down, filtered through Celite® and washed with THF (20 mL). The filtrate evaporated to dryness, taken up in water and extracted with EtOAc (3×). The EtOAc extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography (hexane/EtOAc, 1:3) to afford 5-[2-(methylthio)phenyl]-1H-indole (1.5 g, 52%).
Reaction SMILES: C([Sn]([C:14]1[N:15]=[N:16][CH:17]=[CH:18][CH:19]=1)(CCCC)CCCC)CCC.Br[C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][C@@H:40]([CH3:50])[C@@H:41]3[C:45]([CH:47]3[CH2:49][CH2:48]3)=[O:46])[C@H:37]3[C:28]2=[C:29]2[C:34]([CH2:35][CH2:36]3)=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)=[CH:23][CH:22]=1.O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:47]1([C:45]([C@H:41]2[C@H:40]([CH3:50])[CH2:39][C@H:38]3[C@H:37]4[C:28]([C@@H:27]([C:24]5[CH:25]=[CH:26][C:21]([C:18]6[CH:19]=[CH:14][N:15]=[N:16][CH:17]=6)=[CH:22][CH:23]=5)[CH2:44][C@:42]23[CH3:43])=[C:29]2[C:34](=[CH:33][C:32](=[O:51])[CH2:31][CH2:30]2)[CH2:35][CH2:36]4)=[O:46])[CH2:49][CH2:48]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(Br)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(-c4ccnnc4)cc3)C[C@]2(C)[C@H]1C(=O)C1CC1
Temperature: 110 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[S:15][CH3:16])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.C(N(CC)CC)C>[C:26]([N:13]([C:11]([C:4]1[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=1)=[O:12])[C:14](=[NH:17])[S:15][CH3:16])([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(=N)N(C(=O)OCc1ccccc1)C(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1 -(3,5 -Diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea hydroiodide (II, 494 mg, 1.27 mmol) was dissolved in a mixture of anhydrous DMF(10 mL), and triethylamine (3 mL) followed by treatment with N-(benzyloxycarbonyloxy) succinimide (470 mg, 1.7 mmol) dissolved in DMF(3 mL). The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was concentrated under reduced pressure and the residue suspended in ethyl acetate (30 mL). Silica gel (25 g) was added to the solution and the solvent was evaporated to leave the silica gel impregnated with the crude product that was purified by flash chromatography on a FlashElute™ system from Elution Solution (P.O. Box 5147, Charlottesville, Va. 22905) using a 90 g silica gel cartridge (eluent:hexanes, ethyl acetate=1:2). The purified N-Cbz-1-(3,5-diamino-6-chloropyrazinoyl)-2-methyl-pseudothiourea (III) was yield);1H NMR (360 MHz, DMSO-d6) δ2.33 (s, 3H), 2.61 (s, 3H), 4.99 (s, 2H), 7.39 (m, 10H), 13.7 (s, 1H); API MS m/z=395 [C15H15ClN6O3S+H]30; LC/MS (Method A)>99%, tr=10.1 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>O.O1CCOCC1>[CH2:18]([O:25][C:26]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1

Procedure:
A 1 L 3-neck flask was charged with 25.09 (160 mmol) trans-4-aminomethyl-cyclohexanecarboxylic acid, 77.4 g (560 mmol) K2CO3, 250 mL dioxane and 250 mL water. The suspension was stirred, then 28.5 mL (200 mmol) benzylchloroformate was added dropwise. The reaction mixture was then stirred at room temperature for 6.5 hours then poured into 800 mL water and acidified (slowly) with 1N HCl. The resulting white precipitate was filtered and dried −45.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][N:19](C)[CH3:20])[C:6]=2[CH:22]=1.N#CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][NH:19][CH3:20])[C:6]=2[CH:22]=1
Reactant: CN(C)CCCC1c2ccccc2CCc2ccc(Cl)cc21
Agent: N#CN
Product: CNCCCC1c2ccccc2CCc2ccc(Cl)cc21

Procedure:
3-Chloro-10,11-dihydro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene is converted to the corresponding cyanamide by following the procedure of Example 6 A. Upon hydrolysis, according to the procedure of Example 6 B, there is obtained 3-chloro-10,11-dihydro-5-(3-methylaminopropyl)-5H-dibenzo[a,d]cycloheptene. This may be converted to its hydrochloride salt directly by treatment with ethanolic hydrogen chloride as described in Example 6 B. After recrystallization from a mixture of isopropyl alcohol and ether, the hydrochloride salt melts at 192.5°-193.5°C., dec.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28](C=O)=[CH:27][CH:26]=1)[CH3:24]>>[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCO)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CN(CCO)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A one liter three-necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid, and piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, a 33.62 g quantIty of 4-[N-(2-hydroxyethyl)-N-methylamino] benzaldehyde is added.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H](C2C=CC(F)=CC=2Cl)[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[C:26](OCC)(=O)CC(C)=O.[Cl:35][C:36]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O.ClC1C=C(F)C=CC=1C=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:38]([C:37]2[CH:40]=[CH:41][CH:42]=[C:43]([F:44])[C:36]=2[Cl:35])[C:5]=1[C:3]([O:2][CH2:1][CH3:26])=[O:4]
Reactant: O=Cc1cccc(F)c1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: O=Cc1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1Cl

Procedure:
Compound C-1 was prepared in analogy to compound C by using ethyl acetoacetate and 2-chloro-3-fluorobenzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluorobenzaldehyde.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].S(Cl)([Cl:15])=O.[CH2:17](O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[ClH:15].[NH:1]1[C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1C[C@H]2CCCC[C@@H]2N1
Solvent: ClCCl
Product: Cl
Product: O=C(OCc1ccccc1)[C@@H]1C[C@H]2CCCC[C@@H]2N1

Procedure:
Additionally, as depicted in FIG. 3, the production of (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3), a key intermediate in the production of trandolaprilat and trandolapril, may be produced using a starting material of crystalline ((1S,2S)-2-((S)-1-phenylethylamino)cyclohexyl)methanol (11). The first step of the process involves reaction with a catalyst including, but not limited to, palladium on carbon or palladium hydroxide on carbon in the presence of an alcohol such as methanol to produce ((1S,2S)-2-aminocyclohexyl)methanol (17). The remaining steps in the conversion of compound (17) to the hydrochloride salt, and eventual conversion to (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3) are based upon the teachings of U.S. Pat. No. 4,879,392, which is fully incorporated herein by reference. Generally, the remaining steps can be described as follows. Compound (17) is subjected to treatment with sodium cyanide in the presence of formaldehyde to produce compound (18), as illustrated in FIG. 3. Subsequently, compound (18) is first reacted with trimethylsilyl chloride, and then the product of that reaction is treated with benzyl chloride to produce compound (19). Further, compound (19) is then subjected to three sequential reactions to produce compound (20) as illustrated in FIG. 3. Specifically, compound (19) is first subjected to treatment with hydrochloric acid. Subsequently, methanesulfonyl chloride is added to the reaction mixture. Thereafter, potassium hydroxide is added to the reaction to produce compound (20). After compound (20) is produced, the compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound (5), as disclosed previously. As described previously, compound (5) may then be treated with thionyl chloride, benzyl alcohol, and dichloromethane to produce (2S,3aR,7aS)-benzyl octahydro-1H-indole-2-carboxylate hydrochloride salt (3).