Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.C([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:10][C:11](=[O:13])[OH:12])=O>O>[NH2:8][C@H:9]([C:14]([NH:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:10][C:11](=[O:12])[OH:13]
Reactant: O=CN[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 50 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
A medium composed of 25.5 g of concentrated sulfuric acid and 72.5 g of water was heated to 50° C., followed by a gradual addition of 30.8 g (0.1 mole) of N-formyl-α-L-aspartyl-L-phenylalanine over about 1 hour. The reaction was conducted for further 3 hours at 50°-60° C. to remove the formyl group, so that α-L-aspartyl-L-phenylalanine was formed. The reaction mixture was then cooled to 20° C., and 9.6 g of methanol and 18.7 g of anhydrous magnesium chloride were added. The reaction mixture was heated to 30° C., followed by a reaction at 30°-35° C. for 4 days. As the reaction proceeded, crystals of α-APM hydrochloride precipitated little by little. After the reaction, the reaction mixture was cooled to 20° C., and the precipitated crystals were collected by filtration and washed with chilled water to obtain a wet α-APM.HCl cake containing 23.9 g of α-APM (as converted into its free form). Yield: 81.4% (based on N-formyl-α-L-aspartyl-L-phenylalanine).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]1[CH3:37])(C)C>C1COCC1>[OH:24][C@H:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]1[CH3:37]
Reactant: C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tetrabutyl ammonium fluoride (16.7 mL, 1N in THF, 16.73 mmol) was added to a solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-pyrrolidinecarboxylate in THF and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to yield the title compound (1.55 g, 7.8 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.0 (m, 3H), 1.4 (s, 9H), 1.6 (m, 1H), 1.9 (m, 1H), 3.3 (m, 2H), 3.5 (m, 1H), 3.8 (m, 1H), 4.9 (s, 1H). ES+=202.15.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[C:10]1([CH3:19])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[OH:18]>C1(C)C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:18][C:11]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:19])[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1cc(C)c(O)c(C)c1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(Oc2nc(Cl)nc(Cl)n2)c(C)c1

Procedure:
Reference is now made to the drawing, which is a flow chart of an exemplary completely integrated process of the present invention for conversion of cyanuric chloride to capped polymer. Cyanuric chloride (CYCI) dissolved in a suitable solvent, preferably toluene, is introduced into the system via line 1, and phase transfer catalyst (PTC) is added at 2. Mesitol and aqueous base are added from vessels 3 and 4, the rates of addition being controlled by valves 5 and 6 respectively. The reactant mixture then passes into static mixer 7, the residence time therein being effective to produce a toluene solution of the desired 2,4-dichloro-6-mesitoxy-1,3,5-triazine (DCMT).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[CH:15]=[O:16])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:17]([C:20]1C=C(C=O)NC=1)#[C:18]C>>[C:18]([C:13]1[CH:12]=[C:11]([CH:15]=[O:16])[N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[CH:14]=1)#[C:17][CH3:20]
Reactant: O=Cc1cccn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC#Cc1c[nH]c(C=O)c1
Product: CC#Cc1cc(C=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1

Procedure:
4-Propynyl-1-(β-D-ribofuranosyl)pyrrole-2-carbaldehyde (Compound 18) was synthesized in the same manner as used for Compound 17, starting with 4-propynyl-2-pyrrolecarbaldehyde (Compound 16) (Non-patent Document 40) (266 mg, 2.0 mmol). After purification by RP-HPLC, Compound 18 was obtained (39 mg, 7%, 2 steps).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C:21](=[N:23]O)[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].N>CO.O.[Ni].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([NH2:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=NO)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: [Ni]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Product: C[C@H](N)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 0.03 h
Yield: 63.8 %

Procedure:
To a solution of 61E (3.6 g, 10.0 mmol) in methanol in a pressure vessel was added Raney Ni in water (˜0.2 g), 10% Pd/C (Degussa type, 200 mg), water (7.5 mL) and ammonia in methanol (2.0M, 5 mL). The reaction vessel was carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 2 min). The reaction vessel was again carefully evacuated under vacuum until the solvent bubbled gently. Hydrogen gas was then introduced to a pressure of 70 psi and the reaction was stirred for 18 h at rt. The reaction was filtered through a pad of celite, taking care to keep the captured catalyst wet with methanol at all times. The celite pad was washed with methanol until the product could no longer be detected in the eluent (TLC, 5% MeOH in CH2Cl2, stain with ninhydrin and heat). Solvent was removed under vacuum and purification by flash chromatography (110 g ISCO silica gel cartridge, step gradient 0%-5%-10% MeOH in CH2Cl2) gave the title compound (2.2 g): MS (ES) m/z 345.35 [M+H]+
Reaction SMILES: C(OC(=O)C(C#N)=[C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:17]C)=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8]([CH3:20])([CH3:19])[CH2:7]1)C.[C-]#N.[Na+].CN(C)C=[O:30]>>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([CH3:20])([CH3:19])[CH2:7][C:6]2=[O:30])=[CH:10][C:11]=1[OH:17]
Reactant: CCOC(=O)C(C#N)=C1CC(C)(C)c2cc(OC)c(OC)cc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Product: COc1cc2c(cc1O)C(C)(C)CC2=O
Temperature: 100 °C
Reaction time: 40 h

Procedure:
In a three necked reaction flask equipped with a reflux condenser, a mixture of 5 g of 2,3-dihydro-5,6-dimethoxy-3,3-dimethyl-1H-inden-1-one (see example 1) and 5.5 g of sodium cyanide in 44.5 ml of dimethyl formamide was stirred at 100° C. for 40 hours. Then, the mixture was pored on an aqueous NaH2PO4 solution and extracted 4 times with ethyl acetate, dried over Na2CO3, and concentrated. The raw product was chromatographed in methylene chloride containing 1% of methanol to yield 2.5 g of white crystals. m.p. 105-107° C. MS: 206(M+), 191(100%), 163, 131, 103.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([OH:12])[C@H:7]1[OH:13])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](OC=C)=[O:17]>COCCOC>[C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([O:12][C:16](=[O:17])[CH2:15][Cl:14])[C@H:7]1[OH:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@H]1O
Reactant: C=COC(=O)CCl
Solvent: COCCOC
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(=O)CCl)[C@H]1O
Yield: 80 %

Procedure:
1.03 g (5.5 mmol) of 6-O-acetylgalactal are taken up in 10-15 ml of DME and 20-25 ml of vinyl chloroacetate and stirred with 1 g of lipase P (Pseudomonas spec.) at room temperature for 5-6 h. Filtering off the reusable enzyme, concentration of the solution and chromatography (SiO2, ether/hexane 1:2) result in 6-O-acetyl-3-O-chloroacetylgalactal in 80% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH2:18]([Sn](CC=C)(CC=C)CC=C)[CH:19]=[CH2:20].B(F)(F)F.CCOCC.[F-].[K+]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8]([CH2:20][CH:19]=[CH2:18])([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C=CC[Sn](CC=C)(CC=C)CC=C
Agent: FB(F)F
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1(O)CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
To a stirred solution of 4-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1 g, 4.11 mmol) in THF (10 mL), tetraallyltin (1.08 mL, 4.52 mmol) in dry THF was added, then cooled to 0° C. before borontrifluoride etherate (0.520 mL, 4.11 mmol) was added drop wise. The mixture was stirred at 0° C. for 1 h and then at room temperature for an additional 2 hours. Potassium fluoride (360 mg in 5 mL water) and celite (1 g) was added and the reaction mixture was stirred for an hour. The reaction mixture was filtered and concentrated to dryness and the residue was dissolved in DCM (200 mL), washed with water (100 mL) and brine 100 mL), dried over MgSO4 and evaporated to dryness. The residue obtained on removal of solvent was purified by silica gel column chromatography using 50% EtOAc in hexanes to obtain 4-allyl-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.94 g, 80%).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[OH-].[Na+]>C(O)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([CH3:27])(=[O:26])=[O:25])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CCc2ccccc2S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Yield: 79.7 %

Procedure:
479 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(methylsulfonyl)phenethyl]piperidine obtained in Example 1 and 2 ml of thionyl chloride were dissolved in 50 ml of ethanol, and the mixture was heated under reflux for 2 hours. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate), to give 368 mg of the title compound as white crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(#N)C>[CH2:12]([O:11][P:7]([CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CCOP(=O)(CCNCCO)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN(CCO)CCP(=O)(OCC)OCC
Temperature: -10 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
The mixture of diethyl 2-(2-hydroxyethylamino)ethylphosphonate (6 g, 26.7 mmol) and K2CO3 (3.7 g, 26.7 mmol) in dry acetonitrile (80 ml) was cooled to −10° C. and ethyl bromoacetate (6.7 g, 40 mmol) was added. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 days. The solvent was then removed by evaporation. Water and CHCl3 were added, the organic layer separated, washed with brine and dried over anhydrous MgSO4. After filtration, solvent was evaporated and the residue was purified by column chromatography on silica gel (CHCl3-MeOH), the ethyl 2-((2-(diethoxyphosphoryl)ethyl)(2-hydroxyethyl)amino)acetate was obtained in 64% yield (5.32g).
Reaction SMILES: N#N.Cl.Cl.[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=[O:32]>ClCCl>[Br:5][C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:31]([NH:30][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:19][CH2:20]3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1
Reactant: Brc1cnc2ccc(N3CCNCC3)nn12
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCN(c2ccc3ncc(Br)n3n2)CC1
Temperature: 0 °C
Yield: 6.2 %

Procedure:
To a rapidly stirred, 0° C., N2 blanketed, suspension of 3-bromo-6-piperazin-1-yl-imidazo[1,2-b]pyridazine dihydrochloride (934.9 mg, 2.6 mmol) and Hunig's base [7087-68-5] (1.8 mL, 10.6 mmol) in dichloromethane (26 mL) was added 2-isocyanato-2-methylpropane [1609-86-5] (340 μL, 2.9 mmol). The suspension was permitted to stir and warm to ambient temperature over 17 h and was then partitioned between brine and ethyl acetate. The organic phase was reduced in volume to precipitate product as 442.1 mg of yellow solid. A 129.3 mg aliquot was purified by preparative RP-HPLC to yield 61.8 mg of 4-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-N-(tert-butyl)piperazine-1-carboxamide as a white powder, mp. 199-200° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (s, 8H) 2.51 (s, 1H) 3.30 (s, 1H) 3.39-3.46 (m, 4H) 3.48-3.54 (m, 4H) 7.26 (d, J=10.11 Hz, 1H) 7.61 (s, 1H) 7.88 (d, J=10.11 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 29.15, 43.05, 45.27, 49.94, 99.27, 110.77, 126.00, 131.50, 136.54, 155.16, 156.93. LRMS (ESI) m/z 381.1/383.1 [(M+H)]+, calc'd for C15H21BrN6O: 381.28.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][C:16](=[N:21][OH:22])[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(CCCCOCc2ccccc2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CCCCOCc2ccccc2)CC1

Procedure:
1-(4-Benzyloxybutyl)-4-piperidone oxime is prepared from 1-(4-benzyloxybutyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].F[P-](F)(F)(F)(F)F.[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CN1CCCC1=O.CN(CCN(C)C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:36]3[N:31]([N:32]=[CH:33][CH:34]=[CH:35]3)[N:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: N[n+]1ccccn1
Reactant: CCOc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOc1ccc(C2=NN3N=CC=CC3C2c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h

Procedure:
Titanium tetrachloride (3.45 mL) was added to a stirred mixture of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (10.0 g), N-amino-pyridazinium hexafluorophosphate (7.95 g) in dichloromethane (150 mL) at about 20° C. N-Methyl-pyrrolidinone (3.0 mL) was added at about 20° C. TMEDA (6.7 mL) was then added over a period of about 4 hours at about 20° C. After stirring the mixture for about 1 hour, a second portion of TMEDA (12.3 mL) was added over about 20 minutes, and the reaction mixture was stirred at about 20° C. for about 16 hours.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(OCC)C>[CH2:36]([O:35][C:33]([NH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH3:16])=[CH:11][CH:10]=1)=[O:34])[CH3:37]
Reactant: CC(C)(c1ccc(F)cc1)c1ccc(OC[C@H]2CCC[C@H]2N)cc1
Reactant: CCOC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCC[C@@H]1COc1ccc(C(C)(C)c2ccc(F)cc2)cc1

Procedure:
To a solution of (±) cis -1-amino-2-[4-(1-(4-fluorophenyl)-1-methylethyl)phenoxymethyl] cyclopentane (0.58 g, 1.77 mmol) in dry diethyl ether (30 ml) containing triethylamine (0.49 ml, 3.54 mmol) was added a solution of ethyl chloroformate (0.29 g, 2.66 mmol) in diethyl ether (5 ml). The reaction was worked up as described in Preparation 8, and the resulting yellow oil (0.62 g) was used directly in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([OH:24])=O)=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22]([N:40]1[CH2:51][C@H:50]([OH:52])[CH2:49][C@H:41]1[C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:24])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4R)-1-t-butoxycarbonyl-N-t-butyl-4-hydroxy-L-prolinamide (prepared as described in Preparation 5) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 115°-120° C.
Reaction SMILES: [S:1]1C2C=CC(C(C3C4C(=C(CSC)C=CC=4)NC=3)(C3CC3)C)=CC=2[CH:3]=[CH:2]1.Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([C:39]2[C:47]3[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=3)[NH:41][CH:40]=2)([CH:36]2[CH2:38][CH2:37]2)[CH3:35])=[CH:30][CH:29]=1>>[S:1]1[C:28]2[CH:29]=[CH:30][C:31]([C:34]([C:39]3[C:47]4[C:42](=[C:43]([CH2:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][CH:40]=3)([CH:36]3[CH2:37][CH2:38]3)[CH3:35])=[CH:32][C:33]=2[CH:3]=[CH:2]1
Reactant: CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1
Reactant: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Product: CC(c1ccc2sccc2c1)(c1c[nH]c2c(CS(C)(=O)=O)cccc12)C1CC1

Procedure:
The title compound was prepared starting from 237 mg (0.63 mmol) of the compound from Example 187 in analogy to the synthesis of the compound from Example 209. 144 mg (56% of theory) of the target compound were obtained.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OP(O)(O)=O.[C:20]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=O)[CH2:21][CH3:22].[NH:30]([C:32]1C=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1)N>O>[N:27]1[CH:28]=[CH:29][C:24]([C:20]2[NH:30][C:32]3[C:22]([CH:21]=2)=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)=[CH:25][CH:26]=1
Reactant: CCC(=O)c1ccncc1
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C(O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
20 g of P2O5 were admixed with 12.5 ml of H3PO4 (85%), resulting in a strong increase of the temperature of the reaction mixture. The reaction mixture was then cooled to 60° C., and 8.90 g (65.84 mmol) of 4-propionylpyridine and 4.20 g (27.60 mmol) of 4-hydrazinobenzoic acid were added. The mixture was then stirred at 145° C. for 45 min. The reaction mixture was poured into water, resulting in the precipitation of the yellow product 2-pyridin-4-yl-1H-indole-5-carboxylic acid. This precipitate was filtered off with suction and washed with water until neutral. The 2-pyridin-4-yl-1H-indole-5-carboxylicacid, which was obtained by this method in quantitative yield, was used without further purification for coupling with amino acid derivatives.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.CN(C=O)C.Br[CH2:24][C:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH:26]=1>O>[OH:34][C:31]([C@H:28]1[CH2:29][CH2:30][C:25]([CH2:24][N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])=[CH:26][CH2:27]1)([CH3:33])[CH3:32]
Reactant: CC(C)(O)[C@@H]1CC=C(CBr)CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)[C@@H]1CC=C(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of 2.2 g (16 mmol) K2CO3, 1.2 g (8.4 mmol) phthalimide, and 40 ml DMF was stirred at room temperature for 0.5 hours. Thereafter, 1.7 g (7.4 mmol) (S)-2-(4-bromomethyl-cyclohex-3-enyl)-propan-2-ol (Bull, et. al. Aust. J. Chem., 46 1869, 1993) was added and the resulting mixture was stirred at room temperature for 72 h. Water was added and the mixture was then extracted with ethyl acetate. The ethyl acetate extracts were combined; washed with water and brine; dried (MgSO4); and filtered and concentrated in vacuo. Chromatography on silica gel using 20% ethyl acetate/hexanes yielded 0.62 g (28%) of the desired product.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:30][C:31]([F:32])([F:33])[F:34])=[C:22]([F:21])[CH:23]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)c(F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)c(F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-fluoro-4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.94 min.; [M+H]+: 427.98 g/mol.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:20]=[C:19]([CH:21](Br)[CH:22](Br)[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[C:11]2[CH2:12][C:13]3([O:18][C:10]=2[C:9]=1[O:31][CH3:32])[CH2:17][CH2:16][CH2:15][CH2:14]3.O>C1COCC1>[Br:7][C:8]1[CH:20]=[C:19]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[C:11]2[CH2:12][C:13]3([O:18][C:10]=2[C:9]=1[O:31][CH3:32])[CH2:14][CH2:15][CH2:16][CH2:17]3
Reactant: COc1c(Br)cc(C(Br)C(Br)c2ccncc2)c2c1OC1(CCCC1)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(Br)cc(C#Cc2ccncc2)c2c1OC1(CCCC1)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
Potassium tert-butoxide (0.15 g) was added to a solution of Compound 142a (0.25 g) obtained in Step A in THF (9 ml) at 0° C., followed by stirring at room temperature for 5 hours. The reaction solution was poured into water and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/1) to give Compound 142b (0.12 g, 68.2%) as pale-yellow crystals.