Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+:17].O>S1(CCCC1)(=O)=O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[N:10][C:11]=2[NH2:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(Cl)nccc2n1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)(C)c1ccc2c(N)nccc2n1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
A mixture of 22.1 g (100 mmol) of 2-tert-butyl-5-chloro-1,6-naphthyridine (S36), 32.1 g (600 mmol) of ammonium chloride in 100 ml of sulfolane is stirred at 200° C. for 20 h. 300 ml of water are added to the cooled mixture, which is then stirred at room temperature for 2 h. The solid is filtered off with suction, washed twice with 50 ml of water each time and subsequently suspended in a mixture of 50 ml of methanol and 150 ml of conc. ammonia solution. The suspension is stirred at room temperature for 20 h. The solid is filtered off, washed three times with 50 ml of water each time, dried in vacuo and subjected to sublimation (p about 1×10−2 mbar, T=150° C.). Yield: 16.7 g (83 mmol), 83%. Purity: >97% according to 1H-NMR.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:28]=[C:29]=[O:30])[CH2:24][CH2:25][CH2:26][CH3:27]>ClCCl.C(OCC)C>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:29]([NH:28][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:30])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Reactant: CCCCCN=C=O
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCNC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperidine (i.e. the product of Example 1, Step B) (0.10 g, 0.32 mmol) and pentyl isocyanate (0.036 g, 0.32 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight, then filtered and concentrated under reduced pressure to provide a white solid. The solid was slurried in diethyl ether, filtered and air-dried to provide the title compound, a compound of the present invention, as a white powder (0.081 g), melting at 132-134° C.
Reaction SMILES: C([C:5]1[C:6]([CH3:14])=[N:7][CH:8]=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])C(C)C.C(O[C:18](=O)[C:19]1C=CC(Cl)=N[CH:20]=1)C.C([Mg]Cl)C(C)C>>[CH2:14]([C:6]1[CH:5]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][N:7]=1)[CH:19]([CH3:20])[CH3:18]
Reactant: Cc1ncc(C(=O)O)cc1CC(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CC(C)C[Mg]Cl
Product: CC(C)Cc1ccc(C(=O)O)cn1

Procedure:
6-Isobutyl-nicotinic acid is prepared in analogy to 5-isobutyl-6-methyl-nicotinic acid from commercially available 6-chloronicotinic acid ethyl ester and isobutylmagnesium chloride; LC-MS: tR=0.52 min, [M+1]+=180.30.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[NH2:19][CH2:20][CH2:21][OH:22]>>[C:13]1([CH:2]([NH:19][CH2:20][CH2:21][OH:22])[C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCO
Reactant: FC(F)(F)c1cccc(C(Cl)c2ccccc2)c1
Product: OCCNC(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 70 parts of 1-(chlorophenylmethyl)-3-(trifluoromethyl)benzene and 250 parts of 2-aminoethanol is stirred for 3 hours at 140° C. The reaction mixture is cooled and poured onto water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 60 parts (82%) of 2-[{phenyl[3-(trifluoromethyl)phenyl]methyl}amino]ethanol as a residue.
Reaction SMILES: [CH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.O>C(#N)C>[Br:21][C:13]1[C:14]([CH3:15])=[C:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]([O:17][CH3:18])=[CH:11][C:12]=1[CH3:16]
Reactant: COc1cc(C)cc(C)c1Cc1ccc(C(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: COc1cc(C)c(Br)c(C)c1Cc1ccc(C(C)C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-isopropylbenzyl)-1-methoxy-3,5-dimethylbenzene obtained in Reference Example 213 (3.45 g, 12.9 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (2.29 g, 12.9 mmol) with ice-cooling, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate, and then the organic layer was dried over anhydrous sodium sulfate, was filtered, and then was concentrated under reduced pressure. Ethyl acetate-hexane (1:9) was added to the residue, and the precipitated crystals were filtered, and the filtrate was concentrated to obtain 4.50 g (yield is quantitative) of the title compound. Oily matter.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][OH:12])[N:10]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:13])=[C:9]([CH2:11][O:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1CO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [2-(2-furyl)-5-methyl-4-oxazolyl]methanol (5.18 g), 6-chloro-3-cyanopyridine (4.00 g) and N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 1.27 g) under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and 6-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]nicotinonitrile was obtained as colorless crystals (6.97 g, yield 86%) from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 105–106° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9].[C:17]([CH:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][C:21]1=O)(=O)[CH3:18]>>[OH:11][C:6]1[C:7]2[CH:17]([CH3:18])[C:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][C:21]=3[O:9][C:8]=2[CH:10]=[C:4]([CH2:3][CH:2]([CH3:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1
Reactant: CC(=O)C1CCC(C)CC1=O
Reactant: CCCCCC(C)Cc1cc(O)cc(O)c1
Product: CCCCCC(C)Cc1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
When 5-(2-methylheptyl)resorcinol is reacted with 2-acetyl-5-methylcyclohexanone as described in Example 1 the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([OH:11])=[O:10])[CH:5]=[CH:4][N:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(C(=O)O)ccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(Cl)c1C
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 70.8 %

Procedure:
To a stirred solution of 2-chloro-3-methylpyridine-4-carboxylic acid (780 mg, 4.5 mmol) in anhydrous DMF (5.0 ml), was added potassium carbonate (1.25 g, 9.1 mmol), followed by methyl iodide (0.42 ml, 6.8 mmol) dropwise. A further 4 ml of DMF was added and the reaction mixture was stirred at room temperature under nitrogen for 18.5 hours. The solvent was removed in-vacuo and the residue was then partitioned between CH2Cl2 (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with water (2×30 ml), brine (40 ml), dried (MgSO4), filtered and concentrated in-vacuo. The residue was purified by column chromatography (10 g SNAP cartridge, Isolera, 0-6% ethyl acetate:heptanes) to give the title compound (591 mg, 59%) as a colourless oil. LC-MS 84%, m/z=185.9, 187.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 8.33 (d, J=5.04 Hz, 1H) 7.54 (d, J=5.04 Hz, 1H) 3.95 (s, 3H) 2.60 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH3:40])[CH2:31][CH2:32]3)=[CH:25][CH:26]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)C(C)(C)C)CC3)nc2)cc1
Yield: 73.3 %

Procedure:
Place 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-(6-piperazin-1-yl-pyridin-3-yl)-urea (200 mg, 0.461 mmol), triethylamine (0.071 mL, 0.507 mmol), and 4-N,N-dimethylaminopyridine (6 mg, 0.051 mmol) in CH2Cl2 (10 mL). Add 2,2-dimethyl-propionyl chloride (0.062 mL, 0.507 mmol) and stir at room temperature for 17 h. Subject residue to silica gel chromatography eluting with 0-100% EtOAc:hexane to yield 175 mg (73%) of the title compound. MS(ES+): m/z=518.2 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=1>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a disposable tube were added cyclopropylmethanol (0.44 ml, 5.41 mmol) in DMF (2 ml) and followed by addition of sodium hydride (60% dispersion in mineral oil) (260 mg, 6.50 mmol) slowly. It was stirred at RT for 15 min. Then 5-chloro-2-cyanopyridine (500 mg, 3.61 mmol) was added. It was stirred at RT for 1 h. Then the reaction mixture was diluted with water and extracted with EtOAc and tBuOMe. The organic extract was washed with brine and dried over MgSO4. The solution was filtered and concentrated to give the crude material as a dark brown oil. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 15% to 30% to 45% EtOAc in heptane, to provide 5-(cyclopropylmethoxy)picolinonitrile as white solid mixed with cyclopropylmethanol. It was washed by heptane/tBuOMe (˜5:1), and the white precipitate was collected by filtration to yield 5-(cyclopropylmethoxy)picolinonitrile (380 mg, 2.181 mmol, 60.4% yield) as white crystals. MS m/z=175.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH2:14]([CH2:18][C:19](=O)[CH3:20])[C:15]([CH3:17])=O.O>C1(C)C=CC=CC=1>[CH3:20][C:19]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[C:15]([CH3:17])=[CH:14][CH:18]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COC(=O)C=Cc1ccc(N)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(-n2c(C)ccc2C)cc1
Reaction time: 16 h

Procedure:
A mixture of 21.4 g of methyl 4-aminocinnamate and 50 g of acetonylacetone in 500 ml of toluene is heated under reflux using a Dean Stark water separator for 16 hours. The solution is washed with ice cold dilute hydrochloric acid, brine, and then dried over magnesium sulfate. The organic phase is filtered through silica gel, evaporated at 60° under reduced pressure and the residue is crystallized from hexane to yield methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-cinnamate, m.p. 73°-75°. A solution of the ester in 150 ml of methanol and 100 ml 1N aqueous sodium hydroxide is stirred at room temperature for 16 hours. Methanol is evaporated at 60° under reduced pressure. The basic solution is washed with ethyl acetate, then made acidic with ice cold 5N aqueous hydroxhloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, treated with charcoal, and evaporated to dryness at 60° under reduced pressure. The residue is crystallized from ether/hexane (2:1) to yield (E)-4-(2,5-di-methyl-1H-pyrrol-1-yl)-cinnamic acid, m.p. 189°-191°, also named (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-2-propenoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH2:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][C:19]=1[CH3:27].[B][B][B][B][B][B][B][B][B][B]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][CH:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([CH3:27])[CH:20]=3)[CH3:25])[CH:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cccc(N)c2)C1
Reactant: CC(=O)c1ccc(Cl)c(C)c1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)C1CN(Cc2cccc(NC(C)c3ccc(Cl)c(C)c3)c2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of INT 3 (220 mg, 0.99 mmol) and 1-(4-chloro-3-methyl-phenyl)-ethanone (202 mg, 1.20 mmol) in MeOH (10 mL) was added decaborane (85 mg, 0.70 mmol). The mixture was stirred at 60° C. overnight. More decaborane (85 mg, 0.70 mmol) was added and the mixture was stirred at 60° C. for an additional 3 hours. The mixture was concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford INT 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13](F)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8].[CH3:30][N:31]1[C:35]([C@H:36]2[CH2:41][CH2:40][CH2:39][CH2:38][C@@H:37]2[OH:42])=[CH:34][CH:33]=[N:32]1.[H-].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]([C:19]1[S:23][N:22]=[CH:21][N:20]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:42][C@H:37]2[CH2:38][CH2:39][CH2:40][CH2:41][C@@H:36]2[C:35]2[N:31]([CH3:30])[N:32]=[CH:33][CH:34]=2)=[CH:12][C:11]=1[F:18])(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 42.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO 2010/079443; 600 mg, 1.35 mmol), (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexanol (240 mg, 1.33 mmol) prepared in Example 4a, sodium hydride (63%; 100 mg, 2.63 mmol) and DMSO (6.0 mL), to yield the title compound (340 mg, 42%) as a colorless solid.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15].N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.13 His: 0.96 Phe: 0.98 Ala: 1.01 Tyr: 0.96:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12][C:11](N(N=O)C)=[N:10]2)=[CH:5][CH:4]=1.CN(C)C=O.CC(C)([O-])C.[K+].[N+:31]([CH3:34])([O-:33])=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH3:19])[CH2:14][O:13][CH2:12]/[C:11](=[CH:34]/[N+:31]([O-:33])=[O:32])/[NH:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(C)COCC(N(C)N=O)=N2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(C)COC/C(=C/[N+](=O)[O-])N2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 100 mmol of [5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-N-nitroso-N-methylamine, 200 ml of N,N-dimethylformamide, 50 ml of nitromethane and 115 mmol of potassium tert-butoxide is stirred at room temperature for 15 minutes. It is quenched by adding 20 ml of glacial acetic acid and diluted with dichloromethane and water. The organic phase is separated off, washed with water, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:10]1([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][CH2:12][CH:11]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH:5]([CH3:9])[C:6](=[O:7])[C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: C1=C(N2CCCC2)CCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)C(=O)C1=C(N2CCCC2)CCC1
Yield: 95.2 %

Procedure:
Add dropwise a solution of 1-chloro-1-oxopropan-2-yl acetate (600 g, 3.98 mol) in toluene (1200 mL) to a solution of 1-cyclopent-1-enyl-pyrrolidine (546.7 g, 3.98 mol) and triethyl amine (483.9 g, 4.78 mol) in toluene (2400 mL). Reflux the mixture for overnight. Filter the mixture and concentrate the filtration to give crude 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952 g), which is used in next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 5.27 (m, 1H), 3.56 (m, 2H), 3.16 (m, 2H), 2.83 (m, 1H), 2.58 (m, 3H), 2.10 (s, 3H), 1.93 (m, 2H), 1.82 (m, 4H), 1.36 (d, J=7.2, 3H).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)Nc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 6.9 grams (0.033 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 3.08 grams (0.033 moles) aniline. The reaction mixture was stirred for three days at room temperature. The solid mass that formed was slurried in pentane and filtered. The filter cake was air dried and weighed 9.2 grams (92% crude yield). The product melted at 169°-171° C. with decomposition and the infrared spectrum of the product contained a strong carbonyl band at 1650 cm-1 and a sharp NH band at 3320 cm-1 and the isocyanate band at 2225 cm-1 of the starting material was absent.
Reaction SMILES: [OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][OH:5].[C:26](OCC(F)(F)F)(=[O:30])[CH2:27][CH2:28][CH3:29]>CC(C)=O>[OH:1][C@:2]1([C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C:20](=[CH:21][CH2:22]2)[C@:18]2([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[C:3](=[O:6])[CH2:4][O:5][C:26](=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCCC(=O)OCC(F)(F)F
Solvent: CC(C)=O
Product: CCCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C

Procedure:
A mixture of 1 g (2.879 mM) of 17α,21-dihydroxy-pregna-4,9(11)-diene-3,20-dione and 10 ml of trifluoroethyl butanoate in 100 ml of acetone was reacted at 45° C. in the presence of 5 g of Candida cylindracea lipase for 8-10 hours, adding 1 g of lipase at regular time intervals. After completion of the reaction, the lipase was filtered off and the filtrate was concentrated under vacuum, taking up the residue three times with acetone. The semi-solid residue was purified by chromatography on a silica gel column with a dichloromethane/methanol 99:1 mixture. The less polar components were removed, to obtain the richer fraction which was evaporated to yield 0.95 g (2.29 mM) of 17α-hydroxy-21-butanoyloxy-pregna-4,9(11)-diene-3,20-dione.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[N:9][O:10][C:6]=2[CH:5]=1.[CH3:18]I>O1CCCC1>[F:3][C:4]1[CH:17]=[CH:16][C:7]2[C:8]([CH:11]([CH3:18])[C:12]([O:14][CH3:15])=[O:13])=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: CI
Reactant: COC(=O)Cc1noc2cc(F)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)c1noc2cc(F)ccc12
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (2.32 g, 57.9 mmol, 60% in oil) is added portionwise to a solution of methyl 6-fluoro-1,2-benzisoxazole-3-acetate (12.07 g, 57.7 mmol) in tetrahydrofuran at -2° C. The mixture is stirred for 30 minutes at 2° C., treated with methyl iodide (10.65 g, 75.0 mmol), stirred at 5° C. for 50 minutes and poured onto ice. The aqueous mixture is extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as an oil which is identified by NMR spectral analyses.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([OH:19])[CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH:18]=[CH:17][C:14]=1[CH:15]=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A combination of (2) (14 g, 0.050 mol), benzyl chloride (6.3 mL, 0.055 mol) and potassium carbonate (20.7 g, 0.15 mol) was heated to 100° C. for 3 h. After cooling to room temperature, water (200 mL) and ethyl acetate (400 mL) were added; the organic layer was separated and washed with water (5×200 mL), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to produce the crude product as a yellow oil. This was used without further purification in the next step.
Reaction SMILES: COC1C=CC(C)=CC=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.Cl.[F:30][C:31]([F:46])([F:45])[C:32]1[N:33]=[CH:34][C:35]([NH:38][C@H:39]2[CH2:43][CH2:42][CH2:41][C@@H:40]2[NH2:44])=[N:36][CH:37]=1.[F:47][C:48]1[CH:49]=[CH:50][C:51]([C:57]2[N:62]=[CH:61][CH:60]=[CH:59][N:58]=2)=[C:52]([CH:56]=1)[C:53](O)=[O:54]>>[F:47][C:48]1[CH:49]=[CH:50][C:51]([C:57]2[N:58]=[CH:59][CH:60]=[CH:61][N:62]=2)=[C:52]([CH:56]=1)[C:53]([NH:44][C@H:40]1[CH2:41][CH2:42][CH2:43][C@@H:39]1[NH:38][C:35]1[CH:34]=[N:33][C:32]([C:31]([F:30])([F:45])[F:46])=[CH:37][N:36]=1)=[O:54]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: COc1ccc(C)cc1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Agent: Cl
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(F)ccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-methoxy-5-methyl-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 37) from (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14, 75 mg, 0.27 mmol) and 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 69 mg, 0.32 mmol) to afford the title compound.