Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:25](Cl)(Cl)=[O:26])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:25]2(=[O:26])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: COc1ccc(P(=O)(Cl)Cl)cc1OC
Solvent: CCOC(C)=O
Product: COc1ccc(P2(=O)c3ccccc3CN2c2ccccc2)cc1OC
Yield: 34 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 3,4-dimethoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 3,4-dimethoxyphenyl phosphonic dichloride was conducted at 0° C. The crude product produced as a result of the chromatographic separation was dissolved in ethyl acetate and crystallized from diethyl ether to yield 1-(3,4-dimethoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (3.7 g, 34% yield) as beige plates having a melting point of 84°-86° C. and the following analysis:
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[S:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C=O)C>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[S:4][N:3]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1
Reactant: C1CNCCN1
Reactant: COc1ccccc1-c1nc(Cl)ns1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(N2CCNCC2)ns1
Temperature: 150 °C

Procedure:
A mixture of 3-chloro-5-(2-methoxyphenyl)-1,2,4-thiadiazole (0.21 g, 0.93 mmol), piperazine (400 mg, 4.65 mmol), and DMF (3 mL) was sealed in a microwave vessel and heated by microwave irradiation at 150° C. for 5 minutes. The reaction was cooled to room temperature, diluted with water, and extracted with CH2Cl2. The combined extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure to yield 1-(5-(2-methoxyphenyl)-1,2,4-thiadiazol-3-yl)piperazine. LC/MS: m/z 277.1 (M+H)+ at 2.19 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[C:16]([O:22][CH3:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1.[B-](F)(F)(F)[CH:25]=[CH2:26].[K+]>CC(O)C.C1COCC1>[CH3:23][O:22][C:16]1[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:25]=[CH2:26])=[N:3]2)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A mixture of 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (982 mg, 2.31 mmol) in 10 mL of 4:1 IPA/THF was degassed for 20 minutes with an argon balloon, to which TEA (968 μL, 6.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol) and potassium trifluoro(vinyl)borate (659 mg, 6.94 mmol) were added. The reaction mixture was heated at 90° C. for 3 hours. The mixture was filtered through Celite, and the filter pad was rinsed with ethyl acetate. The filtrate was washed with water and brine 3 times. The organic phase was concentrated to a residue under vacuum. The residue was purified by silica gel chromatography eluting with 15-20% EtOAc/hexanes to give the product (395 mg).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](=[O:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.C1COCC1.[BH4-].[Na+]>CO>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]2[OH:29])[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1=O)C(=O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1O)C(O)CCc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of the compound (165 mg) prepared from Step 1 above, in dry methanol and THF (1:1, 8 ml) at −20° C. was added sodium borohydride (38 mg) and the reaction mixture was stirred at rt for 3 h and then at 45° C. for 1 hour. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The solvents were evaporated in vacuo and the residue taken into water and extracted with ethyl acetate. The combined organic extracts were washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude title compound (165 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.I[CH2:14][CH3:15]>[Na].C(O)C>[CH2:14]([O:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])[CH3:15]
Reactant: CCI
Reactant: COc1ccc(O)c(C(N)=O)c1
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
5-Methoxysalicylamide (41.8 g., 0.250 mole) was dissolved in a solution of sodium (6.37 g., 0.277 g-atom) in ethanol (250 ml.). To the resulting cooled (ice-water) solution was added iodoethane (38.9 g., 0.250 mole) over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature over 0.75 hour and then was heated under reflux for 19 hours. The mixture was concentrated and the residue triturated with water. The mixture was filtered and collected solid recrystallized from acetonitrile to give 2-ethoxy-5-methoxybenzamide (34.5 g., 70.7%), m.p. 128°-130°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9]C)[CH:8]=1.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=O>>[Br:12][C:13]1[O:2][C:3]2[C:8](=[C:7]([OH:9])[CH:6]=[C:5]([OH:11])[CH:4]=2)[C:14]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Product: Oc1cc(O)c2c(-c3cc(F)cc(F)c3)c(Br)oc2c1
Yield: 14 %

Procedure:
This compound was prepared using Method B from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-difluorophenyl)ethanone: Yield 14% following procedures B.2, B.3 and B.5; m.p. 121-122° C.; IR 3379, 1620, 1591, 1429, 1121, 1069 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.25 (s, 1H), 9.24 (s, 1H), 7.02 (t, J=8.8 Hz, 1H), 6.72 (d, J=6.4 Hz, 2H), 6.28 (s, 1H), 6.06 (s, 1H); 13C NMR (126 MHz, δ ppm, CDCl3) 163.4 (dd, J=246.0 Hz, 13.4 Hz), 157.5, 156.7, 154.7, 153.2, 139.3 (t, J=10.6 Hz), 115.8, 114.9 (dd, J=7.5 Hz, 17.0 Hz), 112.0, 102.8 (t, J=25.6 Hz), 98.9, 90.4.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:16][CH3:17].O.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:16][CH3:17]
Reactant: CCOC(=O)c1ccc(Cl)c(NC)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1c(Cl)ccc(C(=O)O)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
3.01 g (11.6 mmol) of ethyl 4-chloro-3-(methylamino)-2-nitrobenzoate were dissolved in 35 ml of tetrahydrofuran and 22 ml of water and this solution was admixed with 0.5 g (20.9 mmol) of lithium hydroxide. It was left with stirring for 8 h and then concentrated. The residue was taken up in water and washed with methylene chloride, and the aqueous phase was then adjusted to a pH of 1 using a KHSO4 solution. The precipitate was isolated by filtration with suction, washed with water, and dried under reduced pressure at 70° C.
Reaction SMILES: [Mg].BrC(Br)C.Br[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[Br:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]([OH:25])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:22][CH:21]=1
Reactant: BrCCCCc1ccccc1
Reactant: O=Cc1ccc(CCBr)cc1
Agent: CC(Br)Br
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: OC(CCCCc1ccccc1)c1ccc(CCBr)cc1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
To a solution of magnesium (4.4 g) in tetrahydrofuran (20 ml) was added dibromoethane (1.6 ml) under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added a solution of 1-bromo-4-phenylbutane (38.8 g) in tetrahydrofuran (30 ml) over 30 minutes, and the mixture was stirred for 40 minutes. The obtained Grignard reagent was dropwise added to a solution of 4-(2-bromoethyl)benzaldehyde (32.3 g) in tetrahydrofuran (250 ml) under ice-cooling over 30 minutes and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (200 ml) under ice-cooling, and the mixture was extracted with ethyl acetate (200 ml). The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (70.5 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=10:1) to give 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-ol (32 g) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+].[Br:15]Br>O>[Br:15][C:11]1[C:7]([C:2]([F:1])([F:12])[C:3]([F:6])([F:5])[F:4])=[N:8][NH:9][CH:10]=1
Reactant: FC(F)(F)C(F)(F)c1cc[nH]n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C(F)(F)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 103.6 %

Procedure:
9.30 g of 3-(pentafluoroethyl)-1H-pyrazole was suspended to 90 ml of water, and 6.0 g of 50% aqueous solution of sodium hydroxide was added to the suspension. The mixture was cooled to 0° C., then 8.79 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium salfate, filtered, and concentrated under reduced pressure to obtain 13.72 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH2:24])[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].C(O)(=O)C.O=[C:38]([CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C(O)C.[Ni]>[C:1]([O:5][C:6](=[O:27])[CH2:7][N:8]([C:22](=[O:26])[C@H:23]([CH3:25])[NH:24][CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)[CH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(N(CC(=O)OC(C)(C)C)C(=O)[C@H](C)N)CC2
Agent: [Ni]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1CCc2cc(OC)c(OC)cc21
Yield: 33.3 %

Procedure:
L-Alanyl-N-(5,6-dimethyloxyindan-1-yl)glycine tert-butyl ester (4.0 g) is dissolved in 80 ml of ethanol, and 0.77 g of sodium acetate, 4.0 g of acetic acid, 4.0 g of ethyl 2-oxo-4-phenyl-butyrate, 12 g of molecular sieve 3A and 6.0 g of Raney nickel are added. Thereafter, the reaction and treatment are carried out as in Example 2 to give 2.0 g of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-N-(5,6-dimethoxyindan-1-yl)glycine tert-butyl ester as slightly yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:21]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:11]([S:10][C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][CH:7]=2)=[C:12]1[CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(Sc2c(C)n(Cc3ccccc3)c3cc(Cl)ccc23)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(Sc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (1.08 g, 2.6 mmol) was dissolved in THF (20 mL) and the solution was cooled to −78° C. Diisobutylaluminum hydride (6.5 mL, 1.0M in THF, 6.5 mmol) was added dropwise and the reaction was stirred for 30 minutes then an additional amount of diisobutylaluminum hydride (6.5 mL, 1.0M in THF, 6.5 mmol) was added. The reaction was allowed to warm to 0° C. then quenched with H2O and HCl(aq.). The reaction was submitted to a standard workup procedure to give the title compound.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](B4OC(C)(C)C(C)(C)O4)[C:15]=3[CH3:29])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:32]=[C:33]([NH:46][C:47]2[CH:51]=[C:50]([CH3:52])[N:49]([CH3:53])[N:48]=2)[C:34](=[O:45])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:36]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:31]4[CH:32]=[C:33]([NH:46][C:47]5[CH:51]=[C:50]([CH3:52])[N:49]([CH3:53])[N:48]=5)[C:34](=[O:45])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[N:36]=4)[C:15]=3[CH3:29])[CH2:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Reactant: Cc1cc(Nc2cc(Cl)nn(COCC[Si](C)(C)C)c2=O)nn1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(Nc3cc(C)n(C)n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Yield: 60 %

Procedure:
Following Example 109, 247.2 mg (0.6 mmol) of 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f, 185 mg (0.5 mmol) of 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 110b, 45.8 mg (0.05 mmol) of tris(dibenzylideneacetone)dipalladium(0), 49.3 mg (0.12 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.596 mmol), 0.67 mL (0.85 mmol) of 1.27 M of potassium phosphate in water, and 10 mL of 1,4-dioxane were reacted to afford 186 mg (60%) of 2-tert-butyl-5-(3-(5-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 110c.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:24](=[O:30])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)[C:24]([NH:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:30]
Reactant: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
A solution of (S)-[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-carbamic acid tert-butyl ester (6.0 g, 14.1 mmol, Example 2, Step B) in CH2Cl2 (28 mL) was treated with trifluoroacetic acid (28 mL). The resulting solution was stirred for 20 minutes and then concentrated. The residue was diluted with EtOAc (300 mL), washed with saturated bicarbonate solution (2×300 mL) and brine (300 mL), dried over Na2SO4, and concentrated to give 4.2 g (91%) of (S)-2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:19][C:18](=[O:20])[C:17]3[N:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:22]=[N:23][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][N:21]1[C:17]2[C:18](=[O:20])[NH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][C:16]=2[N:23]=[CH:22]1)[CH3:29]
Reactant: CCOC(=O)Cn1cnc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1cnc2cc(N3CCNCC3)[nH]c(=O)c21
Reaction time: 1.5 h

Procedure:
4-(3-ethoxycarbonylmethyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester, 4 was dissolved in dry methylene chloride at room temperature under N2. CF3COOH (5 equiv.) was added, and the reaction mixture was stirred for 1.5 h. Then methylene chloride was removed in vacuo and the residue was used in the next step without further purification.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][CH:31]([CH2:35][CH3:36])[C:32](O)=[O:33]>>[CH3:30][CH:31]([CH2:35][CH3:36])[C:32]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:33]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: CCC(C)C(=O)O
Agent: Cl
Product: CCC(C)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-methylbutyric acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-methylbutyroyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 450 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[C:10](=[C:11]3[C:16]=1[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12]3)[CH:9]=[CH:8][CH:7]=[CH:6]2)[CH3:2].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>O1CCCC1.ClCCl>[CH:14]1[CH:13]=[CH:12][C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[NH:4][CH2:3][C:16]=2[CH:15]=1.[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]1[S:56]([C:53]1[CH:52]=[CH:51][C:50]([O:49][CH3:48])=[CH:55][CH:54]=1)(=[O:58])=[O:57])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1nc2ccccc2c2cc(C)ccc12
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1c2ccc(C)cc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
The intermediate dihydrophenanthridine was prepared from 6-ethyl-9-methylphenanthridine, (Example 42, Step b, 0.50 g, 2.3 mmol), by treatement with sodium borohydride (0.51 g, 13.5 mmol) and trifluoroacetic acid (0.7 mL, 9 mmol) in tetrahydrofuran (11 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (1.9 mL, 14 mmol) and 4-methoxybenzenesulfonyl chloride (0.93 g, 4.50 mmol) in dichloromethane (11 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by re-crystallization from a mixture of ethyl acetate-hexane to yield 6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-9-methyl-5,6-dihydrophenanthridine as a homogeneous, white, crystalline, solid, m.p. 133° C.;
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH2:14])=[N-]>CCOCC>[CH:1]1([CH2:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCC1CCCCC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)CCC1CCCCC1
Temperature: 0 °C
Yield: 88 %

Procedure:
To an ice-cooled and stirred solution of 3-cyclohexylpropionic acid (5.0 g, 32.1 mmol) in 30 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent liquid of methyl 3-cyclohexylpropionate (4.8 g, 28.2 mmol, yield 88%, b.p. 95°-99° C./8 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13](C)(C)[O:14][SiH2]C(C)(C)C)[CH:7]=1.Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCCN1c1cncc(Br)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OC[C@@H]1CCCN1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-bromo-5-[(S)-2-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-1-yl]-pyridine (intermediate A-3 [B], 0.1 g, 0.269 mmol) in MeOH (2 mL) was added 4M HCl in dioxane (0.202 mL, 0.808 mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness, the residue diluted with DCM, poured into aq. NaHCO3 (10 mL) and extracted with DCM (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the title compound (0.060 g, 87%) as a yellow oil. MS: 257.0, 259.0 (M+H+).
Reaction SMILES: [Pb](SC#N)[S:2][C:3]#[N:4].ClCl.[CH2:10]1[O:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11]1>C(O)(=O)C>[CH2:10]1[O:18][C:13]2[CH:14]=[CH:15][C:16]([S:2][C:3]#[N:4])=[CH:17][C:12]=2[O:11]1
Reactant: N#CS[Pb]SC#N
Reactant: c1ccc2c(c1)OCO2
Agent: ClCl
Solvent: CC(=O)O
Product: N#CSc1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 161.8 %

Procedure:
Lead thiocyanate (45 g, 139 mmol) was added in portions to a stirred solution of chlorine (20.3 g, 290 mmol) in anhydrous acetic acid (600 ml) under an atmosphere of argon. The mixture was stirred for 15 minutes. 1,2-Methylenedioxybenzene (35 g, 286 mmol) was added in one portion. The mixture was stirred for 1 hour and then filtered. The filtrate was added to ice-water (3.5 liters). The precipitated solid was collected by filtration, dissolved in ethyl acetate and dried (MgSO4). The solvent was removed by evaporation to give 3,4-methylenedioxyphenyl thiocyanate as a pale green oil (40.3 g, 79% yield). The oil solidified and was used without further purification or characterisation.