Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21]>O1CCOCC1>[N:16]1[CH:17]=[CH:18][C:13]([C:2]23[NH:22][CH2:19][CH2:20][N:21]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)=[CH:14][CH:15]=1
Reactant: NCCN
Reactant: COC(=O)c1cccn1CC(=O)c1ccncc1
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccncc3)NCCN12
Yield: 59.8 %

Procedure:
To a solution of methyl 1-[2-oxo-2-(pyridin-4-yl)ethyl]-1H-pyrrole-2-carboxylate (55 mg, 0.23 mmol) in 1,4-dioxane (10 mL) was added ethane-1,2-diamine (0.6 mL, 9.0 mmol). The mixture was heated at reflux for 64 hours and then concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient CH2Cl2 3 CV, 0 to 10% methanol in CH2Cl2 10 CV, hold 10% MeOH 10 CV) to give 10a-(pyridin-4-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as an off-white solid (35 mg, yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 2.84 (dt, 1H, J 15.2, 4.4 Hz), 3.30-3.37 (m, 1H), 3.49 (ddd, 1H, J 11.3, 7.1, 3.5 Hz), 3.79 (dt, 1H, J 11.2, 8.0 Hz), 4.26 (d, 1H, J 12.2 Hz), 4.39 (d, 1H, J 12.3 Hz), 4.48 (dd, 1H, J 2.5, 1.6 Hz), 6.12 (dd, 1H, J 3.8, 2.6 Hz), 6.92 (dd, 1H, J 3.9, 1.5 Hz), 7.25-7.28 (m, 2H), 8.47-8.50 (m, 2H).
Reaction SMILES: [N:1]1([CH:10]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.O>[Br:29][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[N:1]([CH:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)[CH2:2][CH2:3]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3ccccc32)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(Br)ccc32)C1
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of compound 2 (4.15 g, 14.390 mmol) in dry DMF (30 mL) was treated with NBS (2.56 g, 14.390 mmol) in dry DMF (20 mL) at 0° C. and resulting solution was stirred at same temperature for 3 h. The reaction was diluted with water (150 mL) and product was extracted into ethyl acetate (3×30 mL). The combined ethyl acetate layer was washed with water (2×25 mL), brine (25 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (ethyl acetate:hexanes, 1:4) to obtain compound 3 (5.12 g, 97%) as a syrup. 1H NMR (CDCl3) δ 7.18-7.07 (m, 2H), 6.33 (d, 1H, J=8.7 Hz), 4.13-3.99 (m, 1H), 3.68-3.26 (m, 6H), 2.94 (t, 2H, J=8.1 Hz), 2.17-1.99 (m, 2H), 1.46 (s, 9H); ESI-MS (m/z, %): 390 (MNa+, 6), 368 (MH+, 3), 313, 311(100).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1.O>CS(C)=O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[CH:20][C:21](=[O:23])[CH3:22])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2ncccc2c1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of quinoline-6-carboxaldehyde (5.29 g) and 1-triphenylphosphoranylidene-2-propanone (1.5 equiv) in dimethyl sulfoxide (100 ml) was stirred at room temperature for 24 hr. The solution was poured into water (600 ml) which was subsequently extracted with ethyl acetate. The dried (MgSO4) organic fraction was evaporated under reduced pressure and the residue was purified by column chromatography over silica with dichloromethane/ethyl acetate (4:1 v/v) elution to give 1-(quinolin-6-yl)but-1-ene-3-one as a white solid. Pmr spectrum (CDCl3 ; δ in ppm): 2.41 (3H,s); 6.83 (1H,d); 7.3-9.0 (7H,m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:19])=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)O
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 95.4 %

Procedure:
Intermediate 11 (2.98 g) in ethanol (25 ml) was treated with aqueous sodium hydroxide (2.5M, 18 ml) and the solution stirred at 70° C. for 3.5 h then allowed to cool. The material was concentrated in vacuo to remove the ethanol, then the aqueous phase was washed with ethyl acetate (30 ml). The aqueous phase was adjusted to pH1 by addition of aqueous hydrochloric acid (5M) and the desired acid was extracted into ethyl acetate (1×100 ml, 1×50 ml). The combined organic phases were washed with dilute aqueous sodium chloride, dried (Na2SO4), filtered and the solution concentrated in vacuo to give the title compound as a cream solid (2.54 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[Cl:8][CH2:9][C:10]#[C:11][CH2:12]Cl.C([Li])CCC>>[Cl:8][CH2:9][C:10]#[C:11][CH2:12][CH2:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1
Reactant: Cc1cc(C)on1
Reactant: ClCC#CCCl
Agent: [Li]CCCC
Product: Cc1cc(CCC#CCCl)on1

Procedure:
The intermediate 5-(5-chloro-3-pentynyl)-3-methylisoxazole was prepared from 3,5-dimethylisoxazole and 1,4-dichloro-2-butyne in the presence of n-butyllithium.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:34].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[C:20]([OH:22])=[O:34])([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1OC

Procedure:
In analogy with Example 44d), 778 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-dimethoxyphenyl)methyl]dihydrofuran-2-(3H)-one in 27.67 ml of dimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of 1M lithium hydroxide solution to give the title compound, which is subjected directly to further processing. TLC Rf (C)=0.07.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Mg]Br.C[O:12][B:13](OC)[O:14]C.Cl>C1COCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[B:13]([OH:14])[OH:12]
Reactant: COB(OC)OC
Reactant: Cc1cccc(C)c1[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 1.0 M solution of 2,6-dimethylphenylmagnesium bromide in THF (20 ml; 20 mmol) was added over 5 minutes to a solution of trimethylborate (4.5 ml; 40 mmol) in 50 ml of THF at −78° C. The reaction mixture was allowed to warm to room temperature and stir 18 hr. Mter cooling to 0° C., 50 ml of 2 N HCl was added and the resulting mixture was stirred 30 minutes at 0° C. The mixture was partitioned between water (100 ml) and CH2Cl2 (100 ml). The aqueous layer was extracted with CH2Cl2 (2×100 ml) and the combined organic layers were dried (MgSO4) and concentrated to afford a quantitative recovery of the crude title compound of this step. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28]Br)[CH3:22].CCN(C(C)C)C(C)C>CC#N>[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][N:9]1[C@H:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH3:22]
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CCCCN1[C@@H](c2ncccc2C)CCC[C@H]1c1ncccc1C
Reaction time: 23 h
Yield: 94.1 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (306 mg, 1.12 mmol), 5-bromo-pentanoic acid ethyl ester (263 mg, 1.12 mmol), DIPEA (260 μL, 1.49 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (12 mL) was warmed to 60° C. and stirred for 23 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded 5-((2′R,6′S)-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-yl)-pentanoic acid ethyl ester (417 mg, 90%) as a yellow oil. 1H NMR (CDCl3) δ 0.75-0.94 (m, 3H), 1.17 (t, 3H, J=7.1 Hz), 1.55-2.01 (m 8H), 2.20-2.35 (m, 6H), 2.47 (s, 6H), 3.99 (q, 2H, J=7.2 Hz), 7.05-7.09 (m, 2H), 7.43 (d, 2H, J=7.6 Hz), 8.46 (bs, 2H).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N+:14]=1[O-]>O1CCOCC1>[Cl:10][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1
Reactant: COC(=O)c1ccc(C)[n+]([O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCl)nc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
p-Toluenesulfonyl chloride (10.7 g, 56.1 mmol) was combined with 13 (7.8 g, 51.0 mmol) in dioxane (100 ml) under an Argon atmosphere. The reaction mixture was heated under reflux for 1 night. After cooling to room temperature the solvent was evaporated and the residue dissolved in dichloromethane (200 ml). The solution was washed with saturated Na2CO3 (aq) (2×100 ml), brine (50 ml) and dried (Na2SO4). After evaporation of the solvent the product was purified by column chromatography (SiO2, hexane/ethyl acetate 10:2.5) to give 14 (5.71 g, 30.8 mmol, 60%) as a slightly yellow solid. An analytically pure sample could be obtained by recrystallization from n-hexane, mp 63.5-63.8° C.; 1H-NMR (CDCl3) δ3.94 (s, 3H), 4.70 (s, 2H), 7.58 (d, 1H, J=8.4 Hz), 8.30 (dd, 1H, J 8.1 Hz, J=2.2 Hz), 9.08 (d, 1H, J=1.5 Hz); Anal. Calcd. for C8H8ClNO2: C 51.77, H 4.34, N 7.55; found: C 51.50, H 4.23, N 7.46.
Reaction SMILES: [P:1]([Cl:16])(Cl)([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:14])[CH3:13])=[O:2].Cl.[CH2:18]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:19].CCN(CC)CC>C(Cl)Cl>[Cl:16][P:1]([NH:23][C@H:22]([C:21]([O:20][CH2:18][CH3:19])=[O:25])[CH3:24])([O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[CH:6][C:5]=1[CH:12]([CH3:13])[CH3:14])=[O:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1cc(OP(=O)(Cl)Cl)c(C(C)C)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NP(=O)(Cl)Oc1cc(C)c(Cl)cc1C(C)C

Procedure:
Following the procedure described for Example 1, step 2, treatment of a solution in DCM (0.098 M) of 4-chloro-2-isopropyl-5-methylphenyl dichlorophosphate with L-alanine ethyl ester hydrochloride (1.0 eq.) and Et3N (2.0 eq.) provided the title compound as a colorless oil as a 1:1.35* mixture of diastereoisomers. 31P NMR (300 MHz, CD3OD): δ 8.5 and 8.8*.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[CH:17][N:18]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Product: Clc1ccc(-c2nccnc2N2CCNCC2)cc1
Reaction time: 2 h

Procedure:
Dissolve 3′-(4-chloro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester in DCM (10 mL), add 4 M aqueous HCl (5 equiv) and stir for 2 hr. at ambient temperature. Concentrate under reduced pressure, dissolve in methanol (2 mL) and purify by SCX, eluting the product from the ion-exchange resin using 2 M NH3 in methanol, to give the title preparation (0.103 g, 100%). MS (ES): m/z=259 [M+H]+.
Reaction SMILES: [CH:1]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OC1CCCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 28.5 parts of cycloheptanol were mixed under a nitrogen blanket and chilled to 0° C. with an ice water bath. To this solution 53.5 parts of p-toluenesulfonyl chloride were added in portions over thirty minutes. The solution was stirred for one hour at 0° C. and then allowed stand for twenty-four hours at 15° C. The mixture was poured into one liter of ice water and subsequently extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6 N sulfuric acid (until the water layer was acidic to pH paper), dilute sodium bicarbonate (three times with 500 part-portions), and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield cycloheptyl para-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([SH:18])[N:15]([CH3:19])[N:14]=1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:17]=[C:16]([S:18][CH3:22])[N:15]([CH3:19])[N:14]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1S
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C
Temperature: 25 °C
Yield: 97.8 %

Procedure:
A suspension of 0.5 g of 3-(2,6-dichloro-4-trifluoromethylphenyl)-5-mercapto-1-methylpyrazole (2), 2.3 g of methyl iodide and 0.4 g of anhydrous potassium carbonate in 10 ml of acetonitrile was refluxed overnight with stirring. The reaction mixture was cooled to room temperature and filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel to obtain 0.51 g of the desired product in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]O>>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: OCCBr
Product: Clc1cccc(OCCBr)c1Cl

Procedure:
This example was prepared by substituting 1-naphthol with 2,3-dichlorophenol and substituting 3-bromopropanol with 2-bromoethanol in EXAMPLE 31A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([O:20]C)[CH:14]=[C:13]([O:22]C)[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[C:16]([C:17](=[O:19])[CH:18]=1)=[C:15]([OH:20])[CH:14]=[C:13]([OH:22])[C:12]=2[C@@H:24]1[CH2:28][CH2:27][N:26]([CH3:29])[C@H:25]1[CH2:30][OH:31]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cc(C)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(Cl)c(-c2cc(=O)c3c(O)cc(O)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1

Procedure:
Compound of example 37 (0.48 g, 1.1 mmol) was reacted with pyridine hydrochloride (5 g, 43.3 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:17]1([CH2:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:14][C:28]([CH2:27][NH:26][C:24](=[O:25])[CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:29])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)Cc1ccccc1
Agent: Cl
Product: O=C(Cc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from rac-4-chlorobenzhydrylamine hydrochloride and phenylacetylamino-acetic acid (CA [500-98-1]).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCCCCCCN(CC)CCCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCCCCCCN(CC)CCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
In a manner similar to Preparation 2, react 4-[ethyl(heptyl)amino]butanol with 4-fluoronitrobenzene to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([N:15]2[C@@H](C(C)C)COC2=O)=[O:14])=[CH:4][C:3]=1[CH3:35].C[OH:37].NO.[C-]#N.[K+]>C1COCC1.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=2)[C:13]([NH:15][OH:37])=[O:14])=[CH:4][C:3]=1[CH3:35]
Reactant: CO
Reactant: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)N2C(=O)OC[C@@H]2C(C)C)ccc1F
Agent: NO
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COCCCC[C@@H](Oc2ccc(F)c(C)c2)C(=O)NO)ccc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (S)-3-((R)-6-(4-fluoro-3-methylbenzyloxy)-2-(4-fluoro-3-methylphenoxy)hexanoyl)-4-isopropyloxazolidin-2-one (100 mg, 0.20 mmol) dissolved in 2 mL of THF, methanol, and 50 wt % NH2OH in H2O (2:2:1) was added KCN (4.0 mg, 0.06 mmol). The resulting mixture stirred for 3 days at room temperature. The reaction was quenched by the addition of 1M aqueous HCl (10 mL) and the resulting mixture extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×5 mL). The product was isolated by flash column chromatography eluting with 0% to 10% methanol/DCM to give the title compound (54.2 mg) as colorless oil.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=2)[NH:19][CH:18]=1)[C:9]([O:11]C)=[O:10].Cl>O.CO>[N+:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C:15]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:5][CH3:4])([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of lithium hydroxide monohydrate (1.2 g.) in water (20 ml.) was added to a suspension of nitro ester (C) (2.0 g.) in methanol (30 ml.). The mixture was stirred at ambient temperature for 18 hours and then acidified with hydrochloric acid (1N, 50 ml.). The yellow precipitate was isolated by filtration, washed with water, and dried to give 4-(5-nitroindol-3-ylmethyl)-3-methoxybenzoic acid; partial NMR (250 MHz, DMSO-d6): 3.92 (s,3 H, OMe); 4.12 (s,2 H, ArCH2): 11.64 (br s,1 H, NH).
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:36])[N:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:37]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:36])[N:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)C(C)(C)n1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)n1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.7 %

Procedure:
0.50 g of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-3-oxo[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl]-2-methylpropionate was dissolved in 3 ml of ethanol; 2.2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 24 hours. After the ethanol was distilled off under reduced pressure, the residue was diluted with water and washed with ethyl acetate. To the water layer, 2.2 ml of 1 N hydrochloric acid was added; the mixture was saturated with sodium chloride and extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was powdered by the addition of ethyl acetate, collected by filtration, washed with ethyl acetate, and dried, to yield 0.203 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17]([OH:22])[C:18]([CH3:21])([CH3:20])[CH3:19])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][CH:17]([OH:22])[C:18]([CH3:20])([CH3:19])[CH3:21]
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(CC(O)C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N)c(CC(O)C(C)(C)C)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of tert-butyl[4-methoxy-2-(2-hydroxy-3,3-dimethylbutyl)phenyl]carbamate (234 mg) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred for one hour. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (40 mL) and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (157 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24]([C:29]([F:31])([F:30])[F:28])([OH:27])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCN(c2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
1-(4′-Benzyloxybiphenyl-4-yl)piperidin-4-one (7.1 g, 19.9 mmol), tetrabutylammonium acetate (0.3 g, 1.0 mmol) and 1,2-dimethoxethane (100 ml) were mixed. While stirring the mixture under ice cooling, trifluoromethyltrimethylsilane (4.11 ml, 27.8 mmol) was added to the mixture and warmed to room temperature, followed by stirring for 6 hours. The residue obtained by distilling off the solvent was dissolved in tetrahydrofuran (100 ml). While stirring at room temperature, 1 mol/l tetrabutylammonium fluoride in tetrahydrofuran (23.8 ml, 23.8 mmol) was added thereto and stirred at room temperature overnight. Water was added to the residue obtained by distilling off the solvent, followed by extraction with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The resulting crude crystal was washed with diethylether to afford the title compound as a white powder (7.6 g, yield 90%).