Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)[C:5]([F:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=1)#[CH:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:21][C:5]1[C:6]([C@@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[O:11][C:10](=[O:20])[NH:9]2)=[CH:7][C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)=[N:3][CH:4]=1
Reactant: C#Cc1cncc(F)c1
Reactant: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccc(F)cc2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2cc(C#Cc3cncc(F)c3)ncc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 90 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a 15 ml sealable vial was added a 60:40 mixture of (4R,5R)-4-(2-bromo-5-fluoropyridin-4-yl)-5-(4-fluorophenyl)oxazolidin-2-one (50 mg, 0.141 mmol) and its regioisomer in triethylamine (3 mL). To this suspension was added 3-ethynyl-5-fluoropyridine (22.17 mg, 0.183 mmol), triphenylphosphine (11.08 mg, 0.042 mmol) and copper(I) iodide (0.536 mg, 2.82 mmol). The solution was degassed with nitrogen for 20 min, then bis(triphenylphosphine)palladium(II) chloride (1.976 mg, 2.82 mmol) was quickly added and the vial was sealed, heated to 90° C., and allowed to stir overnight. The next day the suspension had turned homogeneous and the reaction was cooled to room temperature and the solvent was evaporated in vacuo. The crude residue was purified by reverse phase chromatography to isolate a single peak (4R,5R)-5-(5-fluoro-2-((5-fluoropyridin-3-yl)ethynyl)pyridin-4-yl)-4-(4-fluorophenyl)oxazolidin-2-one (18.4 mg, 0.046 mmol, 49.8% yield). This single peak was still a mixture of the regioisomers. This single peak was a 65:35 mixture of regioisomers and was subsequently purified by chiral supercritical fluid chromatography Chiralpak AD-H column, 4.6×250 mm, 5 um particle size mobile phase: 35% MeOH in CO2 (w/0.1% diethylamine) column temp: 35 C flow rate: 2 mL/min., affording 1H-NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.51 (d, J=4.0, 1H), 7.79 (d, J=4.0, 1H), 7.64-7.60 (m, 1H), 7.42-7.39 (m, 2H), 7.19-7.15 (m, 2H), 6.00 (brs, 1H), 5.36 (d, J=4.0, 1H), 5.12 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=1.95 min. Mass=395.99 (MH)+.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][CH:19]=[C:20]([C:25]([O:27]C)=O)[C:21]([O:23][CH3:24])=[O:22])=[N:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CCCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[O:27]=[C:25]1[N:13]2[CH:14]=[N:15][C:16]3[CH:17]=[C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3])[CH:9]=[CH:10][C:11]=3[C:12]2=[N:18][CH:19]=[C:20]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(=CNc1ncnc2cc(NC(=O)C(C)(C)C)ccc12)C(=O)OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COC(=O)c1cnc2c3ccc(NC(=O)C(C)(C)C)cc3ncn2c1=O
Temperature: 250 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A mixture of dimethyl [[7-pivalamido-4-quinazolinylamino]methylene]propanedioate (11.7 g) in diphenyl ether (58 ml) was stirred at 250° C. for 15 minutes and cooled to ambient temperature. Hexane was added to the reaction mixture. The resulting crystals were collected by filtration, washed with hexane, and dried. The crystals were dissolved in a mixture of chloroform and ethanol under heating. The solution was filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure until crystallization began. After the solution was cooled to ambient temperature, the resulting crystals were collected by filtration to give methyl 4-oxo-9-pivalamido-4H-pirimido[1,2-C]quinazoline-3-carboxylate (5.1 g). Concentration of the mother liquor gave additional crystals of the same compound (3.4 g).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:32]([O:37]C)(=[O:36])[C@H:33]([CH3:35])O>>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[C:22]([O:28][C@H:33]([CH3:35])[C:32]([OH:37])=[O:36])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O
Reactant: COC(=O)[C@H](C)O
Product: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O[C@H](C)C(=O)O

Procedure:
Prepared from of 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diisopropyl-phenol (Example 40) and commercially available (S)-lactic acid, methyl ester. White solid: mp: 214-215° C.; NMR (CDCl3); δ8.37 (ddd, J=8, 1, 1, 1H), 7.80 (d, J=8 Hz, 1 H), 7.70 (ddd, J=8, 1, 1 Hz, 1 H), 7.66 (ddd, J=8, 8, 1, 1 H), 7.48 (ddd, J=8, 8, 1 Hz, 1 H), 7.37 (ddd, J=8, 8, 1 Hz, 1 H), 7.18 (s, 2 H), 7.01 (ddd, J=8, 8, 1 Hz, 1 H), 6.53 (d, J=8 Hz, 1 H), 4.75 (q, J=7 Hz, 1 H), 3.47 (septuplet, J=7 Hz, 1 H), 3.41 (septuplet, J=7 Hz, 1 H), 1.71 (d, J=7 Hz, 3 H), 1.25 (d, J=7 Hz, 6 H), 1.20 (d, J =7 Hz, 3 H), 1.19 (d, J=7 Hz, 3 H); MS (EI): 560 (90%), 562 (100); Anal. Calc. for C31H29BrO3S: C, 66.31, H, 5.21, N, 0.00. Found: C, 65.90, H, 5.18, N, 0.02.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][CH2:20][C:21]1[CH:29]=[CH:28][C:27]3[O:26][CH2:25][O:24][C:23]=3[CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccc2c(c1)OCO2
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with piperonylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].Cl[CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:22][C:23]#[N:24])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#CCCl
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(c2ccccc2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
2-Methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (4.61 g., 0.015 mole), chloroacetonitrile (1.13 g., 0.015 mole), potassium carbonate (2.08 g., 0.015 mole), potassium iodide (0.25 g., 0.0015 mole) and acetone (75 ml.) are heated at reflux for 23 hours. The reaction mixture is cooled to 25° C. and concentrated to dryness in vacuo to give an oily residue which on trituration with water gives 5.12 g. of (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetonitrile which melts at 163°-165° C. on crystallization from cyclohexane:benzene, 5:1.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:2][NH2:3]
Reactant: COc1cccc(CCl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cccc(CNN)c1
Reaction time: 0.5 h

Procedure:
While a solution of hydrazine monohydrate (10 g, 0.2 mol) in ethanol (35 ml) was heated under reflux, a solution of 3-methoxybenzyl chloride (5.0 g, 32 m mol) in ethanol (15 ml) was added drop-wise thereto over a period of 30 minutes. After this mixture was further refluxed for 2 hours, the solvent was distilled off under reduced pressure. The oily residue was extracted with ether (2×30 ml). After the extract was dried, the solvent was distilled off under reduced pressure. The resulting residue was subjected to chromatography on silica gel (40 g) using chloroform-methanol (20:1), so that there was obtained a crude fraction containing the desired compound. Then, this crude fraction was distilled (120-123° C./1-2 mmHg) to obtain the desired compound (2.9 g, 60%) as a colorless oily material.
Reaction SMILES: [CH3:1][O:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].CO[CH2:11][N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1([O:2][CH3:1])[CH2:8][CH2:11][N:12]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:13]1)=[O:5]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(OC)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
To a stirred solution of methyl 2-methoxyacrylate (20.8 g, 179 mmols) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmols) in dichloromethane (160 ml) was added at 0° C. a solution of trifluoroacetic acid (2 ml) in dichloromethane (10 ml). The resulting solution was warmed to room temperature and stirred overnight. After concentration, the crude product was purified by column chromatography on silica gel eluting with a solution of ethyl acetate/hexanes/Et3N (1000:3000:4 to 1000:1000:3) to give the title compound (10BH) (17.7 mg, 40%). (Note: adding Et3N is essential to ensure sharp separation.)
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:26][C:27]1[S:28][C:29]([CH3:32])=[N:30][N:31]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][S:26][C:27]3[S:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(S)s1
Reactant: O=C(CCCCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: Cc1nnc(SCCCC(=O)NC/C=C\COc2cc(CN3CCCCC3)ccn2)s1
Yield: 78 %

Procedure:
Following a procedure similar to that described in Example 34, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-4-chlorobutyramide (prepared as described in Preparation 2) and 2-mercapto-5-methyl -1,3,4-thiadiazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65°-68° C., in a 78% yield.
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:19])=[O:18]
Reactant: CCOC(=O)CC(C)N
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 36 h
Yield: 45.2 %

Procedure:
A round bottomed flask was charged with ethyl 3-aminobutanoate (1 ml, 6.82 mmol), 1-fluoro-2-nitrobenzene (0.720 ml, 6.82 mmol), potassium carbonate (1884 mg, 13.63 mmol), and a stirbar. THF (35 mL, 0.2 M) was added, and the mixture was stirred at 100° C. for 36 h. The mixture was concentrated with celite and purified by silica gel chromatography to yield ethyl 3-(2-nitrophenylamino)butanoate as a yellow amorphous solid (0.776 mg, 3.08 mmol, 45%).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:22]O>>[Br:6][C:7]1[C:8]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[C:9]([F:17])[C:10]([F:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:22])=[O:13]
Reactant: C[Si](C)(C)c1c(Br)cc(C(=O)O)c(F)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c([Si](C)(C)C)c(F)c1F
Temperature: 25 °C

Procedure:
Sulfuric acid (1.88 mL, 22.3 mmol) was added to a solution of the benzoic acid from step B (5.3 g, 17.1 mmol) in methanol (34 mL) at room temperature. The resulting mixture was stirred at reflux overnight. The mixture was allowed to cool to room temperature then concentrated. The resulting residue was dissolved in EtOAc then washed with saturated NaHCO3 (aq), water, then saturated NaCl (aq). The organics were dried over MgSO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 to afford the title compound as a white solid. 1H NMR (600 MHz, CDCl3): δ 7.78 (dd, J=5.4, 1.0 Hz, 1H); 3.93 (s, 3H); 0.43 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.[CH3:22]N(C)C=O.[H-].[Na+].CI>O>[NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)[nH]c(=O)c23)c(C)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 2-amino-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (847 mg, 3.00 mmol) and N,N-dimethylformamide (30 ml) was added sodium hydride (60% in oil, 120 mg, 3.00 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of MeI (426 mg, 3.0 mmol) and N,N-dimethylformamide (5 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×3). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (3:1) to give 553 mg (62%) of the title compound.
Reaction SMILES: [F-].[K+].F[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].[F:12][C:13](F)([F:22])[O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C1OCCOCCOCCOCCOCCOC1>CS(C)=O.C(OCC)(=O)C>[F:12][CH:13]([F:22])[O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccccc1F
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Oc1cccc(OC(F)F)c1
Temperature: 140 °C
Yield: 67 %

Procedure:
A mixture of potassium fluoride on alumina (40% w/w, Aldrich, 11 g), 2-fluorobenzonitrile (6.0 ml, 56 mmol), 3-trifluoromethoxyphenol (10 g, 56 mmol), and 18-crown-6 (1.48 g, 5.6 mmol) in dimethylsulphoxide (40 ml) was heated to 140° C. for 20 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (300 ml). The solid was filtered off through a plug of celite. The solution was washed with a mixture of water (100 ml) and brine (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:3) as eluent, to give 9.80 g of 2-(3-(difluoromethoxy)phenoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:29][C:2]1([CH3:1])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: COCCC(N)=NO
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 71.1 mg (0.451 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 103 mg (50% of theory).
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][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([N:27]2[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[N:28][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:31]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cnn(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnn(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 1-phenyl-1H-pyrazole-4-carbaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions I): tR=1.27 min.; [M+H]+: 405.81 g/mol.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[CH:36]4)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cccc2cc[nH]c12
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4cccc5cc[nH]c45)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 7-formylindole to the procedure of step 1, Example 66. MS (ES) m/z 506.2.
Reaction SMILES: C([N:5]([CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([NH2:8])=[S:7])(C)(C)C>Cl.CCCCCC.CCOC(C)=O>[CH:9]1([NH:5][C:6]([NH2:8])=[S:7])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)N(C(N)=S)C1CCCC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=S)NC1CCCC1
Reaction time: 0.67 h
Yield: 90 %

Procedure:
The t-butyl-cyclopentylthiourea (3.70 g) was dissolved in concentrated HCl (46 mL). The dark yellow solution was set to a gentle reflux. After 40 min, the reaction mixture was allowed to cool. The volume was concentrated to approx. half under reduced pressure, cooled in ice and basified to pH 9.5 with solid and saturated NaHCO3. The product was extracted into EtOAc (3×), the combined EtOAc extracts were washed with H2O (2×) and brine (1×). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain the crude N-cyclopentylthiourea as a beige solid (2.46 g crude). Trituration of the crude material in hexane/EtOAc 95/5 provided, after filtration, the N-cyclopentylthiourea as a white solid (2.38; 90% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.O>CS(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Fc1ccc(Cn2ccc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 11.72 g (0.1 mol) of indol in 50 ml of dimethyl sulfoxide is added to a mixture of 2.64 g of sodium hydride (0.11 mol, mineral oil suspension) in 100 ml of dimethyl sulfoxide. The mixture is heated at 60° C. for 1.5 hours, then allowed to cool and 15.9 g (0.11 mol) of 4-fluorobenzyl chloride are added dropwise. The solution is warmed to 60° C., allowed to stand overnight and then poured into 400 ml of water with stirring. The mixture is extracted a number of times with a total of 150 ml of methylene chloride, the organic phase is dried using anhydrous sodium sulfate, filtered and the filtrate is concentrated in vacuo. The residue is distilled in a high vacuum: 21.0 g (96% of theory) b.p. (0.5 mm): 140° C.
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH:3]([OH:4])[C:2]([CH3:1])=[CH:5][CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCC=C(C)C=O
Reactant: Cl[Mg]C1CCCCC1
Product: CCC=C(C)C(O)C1CCCCC1
Temperature: 10 °C
Reaction time: 0.83 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 800 ml of 2 M of cyclohexyl magnesium chloride was added and stirred. The flask was cooled to 10° C. 146 g of 99% 2-methyl-2-pentenal was added over the next 135 minutes. The cooling was removed. The first sample was taken 50 minutes later at 13° C. The second sample was taken 35 minutes later at 18° C. 75 minutes later the reaction mixture was quenched with 1000 ml of 20% HAc with cooling. The layers were allowed to settle and the organic layer extracted with 100 ml of toluene. The NMR spectrum of the 1-cyclohexyl-2-methyl-2-penten-1-ol is as follows . . . 0.7-0.9 ppm (q, 1H); 0.9-1.0 ppm (t, 4H); 1.1-1.3 ppm (m, 3H); 1.6 ppm (s, 3H); 1.6-1.8 ppm (m, 4H); 2.0-2.1 ppm (m, 3H); 3.7 ppm (d, 1H); 5.4 ppm (t, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25](=[O:32])[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:43])[CH2:24][C:25](=[O:32])[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CCOCC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CCOCC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-1-[3-oxo-3-(tetrahydro-pyran-4-yl)-propionyl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as yellow oil. MS (ESI): m/z=508.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].C([O-])(=O)C.[Na+].CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>C(O)(=O)C>[N:1]1([CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4])[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: CCCC(N)C(=O)O
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCC(C(=O)O)n1cccc1

Procedure:
2-Aminopentanoic acid (0.2 mole) is added to a solution of sodium acetate (0.2 mole) in about 300 ml of glacial acetic acid. This solution is heated to effect solution and is then refluxed for 5 minutes. To the refluxing solution is added (0.2 mole) 2.5-dimethoxytetrahydrofuran as quickly as possible. The mixture is refluxed for a further 2 minutes and the acetic acid is flash evaporated. The residue is taken up in ethyl acetate, washed with water, dried and the solvent removed under vacuo to give 2-(1-pyrryl)pentanoic acid.