Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16]([O:18][CH2:19][CH:20]1[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)=[O:17])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]=1[NH:15][C:16](=[O:17])[O:18][CH2:19][CH:20]1[CH2:21][NH:22][CH2:23]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])OCC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 3-((((2-nitro-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.50 g, 1.15 mmol, 1 eq.) in dichloromethane (10 mL) was added TFA (3 mL) at 0° C. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure. A saturated solution of sodium bicarbonate was added. The obtained solid was filtered and dried under reduced pressure to afford azetidin-3-ylmethyl (2-nitro-5-(thiophen-2-yl)phenyl)carbamate (0.35 g, 91%
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>ClCCl.CN(C=O)C.C(N(CC)C(C)C)(C)C>[CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])=[N:17][CH:18]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(-c2ccccc2)c(-c2ccc(NN)nc2)o1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccc2)c(-c2ccc(NNC(=O)C(C)C)nc2)o1

Procedure:
To a stirred, cold (0° C.) solution of 5-(2-Methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl-hydrazine in 0.5 mL of dichloromethane and 0.3 mL of DMF and 0.325 mL of N,N-diisopropylethylamine was added 0.02 mL of isobutyryl chloride. After 5 minutes an additional 0.005 mL of isobutyryl chloride was added and the reaction was quenched a minute later with water. The mixture was extracted with dichloromethane (3×), washed with water (2×), brine (1×), dried (sodium sulfate), filtered, and the filtrate was concentrated to a dark orange oil. This oil was purified by flash chromatography (eluting with 5:1 ethyl acetate/hexanes) to give 23 mg of isobutyric acid N′-[5-(2-methyl-4-phenyl-oxazol-5-yl)-pyridin-2-yl]-hydrazide as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]([CH2:11][CH:12]=O)[C:5](=[O:14])[C:4]=2[CH:3]=1.[CH2:15]([N:17]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[C:19]2[CH:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[CH:31]=[CH:32][C:18]1=2)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OC(=O)C)C.[ClH:65]>C(OCC)(=O)C.ClCCCl.C(O)(=O)C>[ClH:65].[ClH:65].[CH2:15]([N:17]1[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[N:20]([CH3:28])[C:19]2[CH:29]=[C:30]([CH2:33][CH2:34][CH2:35][CH2:36][N:37]([CH2:12][CH2:11][N:6]3[CH:7]=[CH:8][C:9]4[O:10][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]3=[O:14])[CH2:38][C:39]3[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=3)[CH:31]=[CH:32][C:18]1=2)[CH3:16]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCNCc3ccncc3)ccc21
Reactant: Cc1cc2c(=O)n(CC=O)ccc2o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CCCCN(CCn3ccc4oc(C)cc4c3=O)Cc3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Methyl-4-oxo-4H-furo[3,2-c]pyridin 5-yl)acetaldehyde (0.18 g) and acetic acid (0.1 ml) were added to a 1,2-dichloroethane solution (5 ml) of 1-ethyl-3,3,5-trimethyl-7-{4-[(pyridin-4-ylmethyl)amino]butyl}-1,5-dihydrobenzo[b][1,4]diazepine 2,4-dione (0.38 g). The mixture was stirred for 30 minutes at room temperature. sodium triacetoxyborohydride (0.32 g) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0→9:1). The purified product was condensed under reduced pressure. A 6N-hydrogen chloride ethyl acetate solution (1.0 ml) was added to an ethyl acetate solution (20 ml) of the residue, and the liquid was stirred at room temperature. The precipitated insoluble matter was separated, washed with ethyl acetate, and dried to give the title compound (0.43 g) as a white solid.
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][CH:14]=2)[CH:8]=1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[S:1])[NH2:30])[CH:24]=2)(=[O:22])=[O:21])[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][N:16]=[N:15][CH:14]=2)[CH:8]=1
Reactant: Cc1cc(OCCNc2ccnnc2)cc(OS(=O)(=O)c2cccc(C#N)c2)c1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(OCCNc2ccnnc2)cc(OS(=O)(=O)c2cccc(C(N)=S)c2)c1
Yield: 87 %

Procedure:
Hydrogen sulfide was passed into a solution of 1.5 g (3.7 mmol) 3-cyanobenzenesulfonic acid-3-methyl-5-[2-(pyridazin-4-ylamino)-ethoxy]-phenyl ester (example 9) and 2.0 ml triethylamine in 20 ml pyridine until saturation (ca. 30 min). After 2 h at room temperature the solvent was removed in a vacuum, the residue was admixed with water, extracted with ethyl acetate, the solvent was removed in a vacuum, the residue was taken up in methanol and filtered over silica gel (dichloromethane: methanol=98:2). The solvent was removed in a vacuum and the title compound was obtained in a 87% yield as yellow crystals of Fp 76°-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:10]([OH:25])[C:11]([NH:13][NH:14]C(OCC1C=CC=CC=1)=O)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd].[C]>[CH:27]1([CH2:26][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]([OH:25])[C:11]([NH:13][NH2:14])=[O:12])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)NN
Reaction time: 16 h

Procedure:
A solution of Example 13A (0.37 g, 0.82 mmol) in methanol (15mL) was treated with Pd-carbon (0.05 g), stirred under a hydrogen atmosphere for 16 hours, filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:24][CH2:25][C:26]([CH3:31])([CH3:30])[C:27](Cl)=[O:28]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:27](=[O:28])[C:26]([CH3:31])([CH3:30])[CH2:25][F:24])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Reactant: CC(C)(CF)C(=O)Cl
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C(C)(C)CF)C2)cc1

Procedure:
62 mg (0.20 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 42 mg (0.3 mmol, 1.5 eq.) of 3-fluoro-2,2-dimethylpropanoyl chloride were reacted according to General Method 2. Yield: 68 mg (83% of theory)
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[C:13]=2[C:15]([F:18])([F:17])[F:16])[N:8]=[C:7]([CH3:31])[C:6]=1[CH3:32])(=O)C.[OH-].[Na+].O.Cl>C(O)C>[F:17][C:15]([F:16])([F:18])[C:13]1[C:12]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:22][CH:21]=2)=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([OH:4])=[C:6]([CH3:32])[C:7]([CH3:31])=[N:8]2
Reactant: CC(=O)Oc1c(C)c(C)nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C(F)(F)F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
4-Acetoxy-5-trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-2,3-dimethyl-quinoline (1.5 g) prepared in Synthesis Example 2 was dissolved in 10 mL of ethanol. A 20% sodium hydroxide solution (10 mL) was added to the solution, and the mixture was stirred at 50° C. for 3 hr. This reaction mixture was added to 20 mL of water, and the mixture was neutralized with 1 N hydrochloric acid. The precipitated crystals were collected by filtration under the reduced pressure to give 1.34 g of 5-trifluoromethyl-6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3-dimethyl-quinoline (yield 98.0%).
Reaction SMILES: Br.[O:2]([CH2:4][CH2:5][Br:6])[NH2:3].C(O)(=O)C.N1C=CC=CC=1.[CH3:17][CH:18]1[C:25]2[N:24]3[CH:26]=[CH:27][CH:28]=[C:23]3[CH2:22][C:21]=2[S:20][C:19]1=O>C(O)C>[CH3:17][C:18]1[C:25]2[N:24]3[CH:26]=[CH:27][CH:28]=[C:23]3/[C:22](=[N:3]/[O:2][CH2:4][CH2:5][Br:6])/[C:21]=2[S:20][CH:19]=1
Reactant: NOCCBr
Reactant: CC1C(=O)SC2=C1n1cccc1C2
Agent: Br
Solvent: CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1csc2c1-n1cccc1/C2=N/OCCBr
Yield: 23 %

Procedure:
Add 5 g of 2-aminoxy-1-bromoethane hydrobromide, 1.5 mol of glacial acetic acid and 1.6 ml of pyridine in succession to a suspension of 1.43 g of 3-methyl-8H-thieno[2,3-d]pyrrolo[1,2-a]pyrrol-2-one (Preparation 29) in 70 ml of ethanol. The reaction mixture is heated at reflux for 3 hours, then the ethanol is removed under reduced pressure and the residue is extracted with 100 ml of diethyl ether. After washing with water, drying, concentrating to dryness and working up again in a diethyl ether/petroleum ether mixture, 1:1, the title compound is obtained in the form of a powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([O:20][C:21]2[CH:26]=[CH:25][C:24]([O:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(Oc2ccc(OC3CCNCC3)cc2)cc1
Temperature: 0 °C
Yield: 153.8 %

Procedure:
To a solution of t-butyl-4-hydroxy-1-piperidinecarboxylate (0.40 g, 1.99 mmol) in anhydrous THF (8 mL) was added 4-(4-chloro-phenoxy)-phenol (0.58 g, 2.61 mmol) and triphenylphosphine (0.63 g, 2.40 mmol). The resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (0.47 mL, 2.43 mmol) was added portionwise over a ten minute period. The reaction mixture was warmed to ambient temperature for an hour and then heated to 47° C. for 64 h. The solvent was removed in vacuo. The crude residue was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.93 g, 100%) as a yellow oil.
Reaction SMILES: [CH:1]1(/[CH:5]=[C:6](/[C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)\[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:5][CH:6]([C:17]2[NH:26][C:20]3=[N:21][CH:22]=[C:23]([F:25])[CH:24]=[C:19]3[CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 17.4 %

Procedure:
A mixture of [2-(E)-cyclobutyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (prepared as in Example 46, 200 mg, 0.54 mmol) and 10% palladium on activated carbon (70 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 8 h. The mixture was cooled to room temperature. The catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[2-cyclobutyl-1-(4-methanesulfonyl-phenyl)-ethyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (35 mg, 17.5%) as a light yellow solid: LC/MS m/e calcd for C20H21FN2O2S [M+H]+ 373.46, observed 372.8; 1H NMR (400 MHz, CD3OD) δ ppm 8.03 (t, J=2.1 Hz, 1H), 7.88-7.93 (m, J=8.3 Hz, 2H), 7.67-7.79 (m, 1H), 7.56-7.61 (m, J=8.3 Hz, 2H), 6.42 (s, 1H), 4.20 (t, J=7.7 Hz, 1H), 3.06-3.19 (m, 3H), 2.16-2.40 (m, 3H), 1.93-2.08 (m, 2H), 1.64-1.90 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1>C(O)C>[CH3:1][NH:2][CH:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1
Reactant: CNC1C=Cc2ccccc2CC1
Solvent: CCO
Product: CNC1CCc2ccccc2CC1
Yield: 84.3 %

Procedure:
A mixture of 3.4 g of 7-methylamino-6,7-dihydro [5H] benzocycloheptene, 200 ml of ethanol and 3.4 g of 10% palladized carbon was maintained under a hydrogen atmosphere until absorption ceased and was then filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 2.9 g of 7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene. The said product was dissolved in 300 ml of ether and an ether solution saturated with hydrogen chloride was added. The mixture was filtered and the recovered precipitate was crystallized from an 8-2 ethyl acetate-methanol mixture to obtain 2.6 g of the hydrochloride of 7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene melting at 270° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:18].[C:19]1([CH2:25][C:26](=[NH:30])OCC)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[ClH:18].[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26](=[NH:30])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=N)Cc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Agent: Cl
Solvent: CCO
Product: N=C(Cc1ccccc1)Nc1ncccc1OCc1c(F)cccc1F
Yield: 5.5 %

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (4.72 g, 20 mmol) and ethyl phenylacetimidate hydrochloride (4.39 g, 22 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was purified by flash chromatography (chloroform/methanol) to obtain the product as a hygroscopic glass (0.43 g), m.p. 45°-50° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].CI.[C:25](=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[CH3:25][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][C@H:9]2[CH2:8][CH2:7][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:11][CH2:10]2)=[CH:21][CH:20]=1
Reactant: CCCCC[C@H]1CC[C@H](CCCCc2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Solvent: O
Product: CCCCC[C@H]1CC[C@H](CCCCc2ccc(OC)cc2)CC1

Procedure:
A mixture of 0.3 g of 4-[4-(trans-4-pentylcyclohexyl)-1-butyl]phenol, 0.14 g of methyl iodide, 0.6 g of potassium carbonate and 50 ml of absolute butanone was heated to reflux overnight. Subsequently, the cooled reaction mixture was poured into water and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with 500 ml of water, dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from ethanol gave pure 1-methoxy-4-[4-(trans-4-pentylcyclohexyl)-1-butyl]benzene with m.p. (C-I) 27° C. and cl.p. (SB -I) 16° C.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][OH:16]>CO>[C:1](=[N:15][OH:16])([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
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CO
Product: ON=C(c1ccccc1)c1ccccc1
Temperature: 5 °C

Procedure:
A 500 mL 3-neck flask was fitted with thermometer, dropping funnel and nitrogen blanket. Benzophenone (36.5 g; 0.2 mol) in absolute methanol (100 mL) was placed in the flask and cooled in an ice bath (5° C.) with stirring using a magnetic stirring bar. Hydroxylamine solution (133 mL) was slowly added and after completion of addition (15 minutes), the mixture was heated at reflux (65° C.). pH 8.6. After a total of 18 hours of heating under reflux, it was cooled and transferred to a 500 mL round bottom flask and concentrated on a rotovap. On cooling in ice bath, it was filtered and benzophenone oxime was collected as white crystalline solid (32.5 g; 89% yield). Purity, >97%.
Reaction SMILES: C([O:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:32])([CH3:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:14]2[CH:15]([C:21]([OH:23])=[O:22])[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:13]=2[CH:12]=[C:11]([C:24]([CH3:31])([CH3:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:10]=1
Reactant: CCCCCCC(C)(C)c1cc(OCc2ccccc2)c2c(c1)OC(C)(C)CC2C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)CC2C(=O)O

Procedure:
A mixture of 5.0 g. 5-benzyloxy-2,2-dimethyl-7-(1,1-dimethylheptyl)-3,4-dihydro-2H-benzopyran-4carboxylic acid (prepared by the method of Example 88, Part A), 500 mg. 5% palladium-on-carbon catalyst and 150 ml. ethyl acetate is hydrogenated for 18 hours by the procedure of Example 86. After removal of catalyst and evaporation of solvent 4.25 g. of foam is obtained. Purification by silica gel chromatography, eluting with 2:1 hexane/ethyl ether affords 1.84 g. of product, M.P. 147°-148° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10](OCC)=[O:11].[C:23]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:16]([CH2:29][C:25]2[CH:24]=[C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=2)[C:10](=[O:11])[CH:9]([CH3:15])[CH2:8]1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Product: CC1CC(c2ccccc2-c2ccccc2)N(Cc2cccc(-c3ccccc3)c2)C1=O

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.05 min.; [M+H]+: 417.80 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][O:13][C@H:12]([CH2:15][C:16](O)=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][C@@H:12]([CH2:15][CH2:16][OH:17])[O:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC(=O)O)OC1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CCO)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
A solution of borane dimethyl sulphide complex in tetrahydrofuran (2.0 M, 289 μL, 0.58 mmol, 3.0 eq) is added dropwise at 0° C. to a stirred solution of (2S,5R)-(5-tert-butoxycarbonylamino-tetrahydro-pyran-2-yl)-acetic acid (50 mg, 0.19 mmol, 1.0 eq) in tetrahydrofuran (2 mL). The reaction mixture is stirred at 0° C. for 30 minutes then at room temperature for 2 hours. Methanol (2 mL) is cautiously added to the reaction mixture that is then evaporated, repeatedly treated with methanol and concentrated to dryness to afford (3R,6S)-[6-(2-hydroxy-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester as a white solid (47 mg, 99% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitrobenzene (10 g, 70.9 mmoles) is refluxed for 5 hours with 35.7 g (0.41 moles) of morpholine. After that, the reaction product is poured onto 400 g of ice/water and the solid obtained is filtered off. After a recrystallization from ethanol, a dark yellow, finely pulverized dye is obtained with a melting point of 152°-154° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:5][CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1.[OH-].[K+].O.C(O)C>CCOCC>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:8]([CH2:7][CH2:6][NH:5][C@H:4]([C:3]([OH:32])=[O:2])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:9][N:10]=[C:11]1[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCCCc1ncc(CCN[C@@H](Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl

Procedure:
The procedure of Example 2 (ii) was followed using 0.9 g (1.99 mmol) of N-[2-{1-[(2-chlorophenyl)methyl]-2-n-butyl-1H-imidazol -5-yl}ethyl]phenylalanine methyl ester, 0.33 g of potassium hydroxide, 15 ml of water and 25 ml of ethanol to afford after workup 0.54 q of product. Trituration with ether provided the title compound; mp 78°-80° C. (free base) and mp 232°-233° C. (for the dihydrochloride salt).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[N:32]=[C:33]=[O:34]>C1COCC1>[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:34])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([NH:15][C@@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(N)cc2)n1)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)c1csc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)n1)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(S)-methyl 2-(2-(4-aminophenyl)thiazole-4-carboxamido)-3-methylbutanoate (150 mg, 0.450 mmol) was taken in 3 mL THF, to this 2,4-difluoro-1-isocyanatobenzene (76.8 mg, 0.495 mol) was added and stirred at RT for 3-4 hr. After completion of reaction solvent was removed under reduced pressure and the residue purified by column chromatography. Yield: 200 mg (91%). MS (ESI) m/z: 487(M−H)−; 1HNMR (DMSO-d6, 300 MHz): δ 9.369 (s, 1H), 8.594 (d, 1H), 8.316 (s, 1H), 8.291 (s, 1H), 8.126 (m, 1H), 8.023 (d, 2H), 7.640 (d, 2H), 7.372 (m, 1H), 7.106 (m, 1H), 4.431 (dd, 1H), 3.696 (s, 3H), 2.300 (m, 1H), 0.981 (dd, 6H).