Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH:10]=O.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].[BH4-].[Na+]>CO>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:31][CH2:30][CH2:29]1)[CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:10][C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: NCCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1cnc2c(c1)CCCC2N(CCCCNCc1cc2ccccc2[nH]1)Cc1nc2ccccc2[nH]1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of indole-2-carboxaldehyde (prepared as described for COMPOUND 65) (31 mg, 0.21 mmol) and N1-(1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydroquinolin-8-yl)-butane-1,4-diamine (see COMPOUND 17) (51 mg, 0.15 mmol) in MeOH (1.8 mL) was stirred at room temperature under nitrogen for 23 hours. NaBH4 (14 mg, 0.37 mmol) was added, and the reaction stirred for a further 15 minutes before the solvent was evaporated under reduced pressure. The residue was dissolved into CH2Cl2 (25 mL) and was washed with saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. The yellow residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 19:1:0.1) giving COMPOUND 31 as a white solid (37 mg, 0.077 mmol, 53%). 1H NMR (CDCl3) δ 1.35-1.49 (m, 4H), 1.60-1.76 (m, 1H), 1.81-1.96 (m, 1H), 1.96-2.08 (m, 1H), 2.11-2.22 (m, 1H), 2.45 (t, 2H, J=6.5 Hz), 2.50-2.60 (m, 1H), 2.66-2.76 (m, 2H), 2.76-2.90 (m, 1H), 3.83 (s, 2H), 3.93-4.10 (m, 3H), 6.27 (s, 1H), 7.02-7.16 (m, 3H), 7.16-7.24 (m, 2H), 7.32 (d, 1H, J=7.8 Hz), 7.41 (d, 1H, J=7.8 Hz), 7.53 (d, 1H, J=7.8 Hz), 7.55-7.62 (m, 2H), 8.56 (d, 1H, J=3.6 Hz), 9.01 (br. s, 1H). 13C NMR (CDCl3) δ 21.6, 23.8, 26.2, 27.5, 29.6, 47.2, 48.9, 49.8, 50.8, 62.3, 100.6, 111.2, 119.8, 120.4, 121.7, 122.0, 122.6, 128.8, 135.1, 136.5, 137.8, 147.1, 156.9, 157.8. ES-MS m/z 479 (M+H). Anal. Calcd. for C30H34N6.0.5CH2Cl2.0.2C4H10O: C, 70.15; H, 6.96; N, 15.68. Found: C, 70.16; H, 6.97; N, 15.73.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.CO[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]=1.N12CCCCC1C=CCCN2>CO>[C:7]([C:6](=[C:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]1)[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)#[N:8]
Reactant: COC1=NCCCCC1
Reactant: N#CCc1ccc(Cl)cc1
Agent: C1=CC2CCCCN2NCC1
Solvent: CO
Product: N#CC(=C1CCCCCN1)c1ccc(Cl)cc1
Yield: 67.6 %

Procedure:
Agitate a mixture of 5.0 g of 4-chlorobenzyl cyanide, 5.5 g of caprolactim methyl ether and 0.5 g of diazabicyclo [5.4.0]undec-5-ene under nitrogen for 18 hours at 125°. Cool the thus-obtained reaction mixture to ambient temperature and then rub down the crystallizing residue with 20 ml of methyl alcohol before filtering to obtain 5.5 g of the title compound. Recrystallize this compound from methyl alcohol to obtain a product with a MP of 114° to 117°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[N:9]2[NH:15]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[NH2:15][N:9]1[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NN1C(=O)CCCC1c1ccc(F)cc1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Step AAG (3): To a soln of tert-butyl 2-(4-fluorophenyl)-6-oxopiperidin-1-ylcarbamate (330 mg, 1.07 mmol) in CH2Cl2 (5 mL) was added TFA (1.00 mL, 13.0 mmol). The mixture was stirred at for 2 hrs. The solvent was removed in vacuo. The crude reaction was diluted with EtOAc (100 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, and concentrated in vacuo to afford 1-amino-6-(4-fluorophenyl)piperidin-2-one (200 mg, 90% yield). LC-MS (M+H)+ 209.26.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1.[Br:16]N1C(=O)CCC1=O.[NH4+].[OH-]>CCCCCCC>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[CH:8][N:7]=[CH:6]2
Reactant: c1ccc2cnccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCCC
Product: Brc1cccc2cnccc12
Temperature: -10 °C

Procedure:
Concentrated H2SO4 (260 mL) was cooled to −25° C. while stirring with a mechanical stirrer. Isoquinoline (30 mL, 0.25 mol) was added slowly so the temperature did not exceed 0° C. After the addition was complete the red solution was recooled to −25° C. and treated with N-bromosuccinimide (55.49 g, 0.31 mol) in small portions so that the temperature did not exceed −20° C. The reaction mixture was stirred for 5 hours keeping the temperature between −30° C. and −18° C. The reaction mixture was then allowed to warm to −10° C. and was poured carefully over 600 g of ice. The resulting slurry was adjusted to pH 10 using 25% NH4OH. The mixture was then extracted with diethyl ether (3×600 mL). The ether fractions were combined, filtered through a celite plug and the filtrate concentrated under reduced pressure. The residue was suspended in hot heptane (600 mL). The heptane was decanted. This procedure was repeated with hexane (2×200 mL). The combined heptane and hexane fractions were concentrated under reduced pressure to give a mustard yellow solid. The title compound was obtained by recrystallization from heptane (26.37 g, 50%). mp 78°-80° C.; MS (ESI+) m/z 209 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 7.65 (t, J 7.9, 1H), 7.94 (d, J 8.1, 1H), 8.17 (dd, J 1.0, 7.4, 1H), 8.22 (d, J 8.1, 1H), 8.68 (d, J 6.1, 1H), 9.37 (s, 1H); Anal. Calcd for C9H6BrN: C, 51.96; H, 2.91; N, 6.73; Br, 38.41. Found: C, 51.24; H, 2.79; N, 6.52; Br, 38.81.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]([N:19]1[CH2:27][C:26]2[C:21](=[C:22]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:15])[F:14])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1.[OH-].[Na+]>C1COCC1>[C:29]([NH:28][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[C:20](=[O:32])[N:19]([CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([F:14])[F:15])=[C:8]([O:16][CH2:17][CH3:18])[CH:7]=1)[CH2:4][C:3]([OH:33])=[O:2])[CH2:27]2)(=[O:31])[CH3:30]
Reactant: CCOc1cc(C(CC(=O)OC)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To the THF solution of 3-(7-acetylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid methyl ester (2.5 g, 5.4 mmol) was added dropwise 10N NaOH (1 ml, 10 mmol) and was stirred at room temperature overnight. The resulted suspension was filtered and the solid was dissolved in water (20 ml). The aqueous solution was acidified to pH=4 to obtain a milky suspension. The suspension was extracted with EtOAc (50 ml×3). The organic layer was washed with water (50 ml×2), brine (30 ml), dried over Na2SO4 and concentrated to give white solid (2.3 g, 96% yield): mp 105-107° C.; 1H NMR (CDCl3): δ 1.42 (J=7.5 Hz, 3H, OCH2CH3), 2.22 (s, 3H), 3.11 (dd, J=5, 12 Hz, 1H, CH2), 3.25 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.5 Hz, 2H, OCH2CH3), 4.12 (d, J=17.5 Hz, 1H, CH2N), 4.38 (d, J=17.5 Hz, 1H, CH2N), 5.81 (m, 1H, CHN), 6.55 (t, JH-F=75 Hz, 1H, CF2H), 6.96 (m, 3H, Ar), 7.13 (d, J=7.5 Hz, 1H, Ar), 7.45 (m, 1H, Ar), 8.43 (d, J=7.5 Hz, 1H, Ar), 10.25 (s, 1H, NHCO). 13C NMR (CDCl3): δ 14.6, 24.8, 36.7, 46.8, 51.7, 64.9, 111.8, 111.3, 115.9, 117.1, 117.3, 118.0, 118.9, 120.1, 122.8, 133.5, 136.7, 137.8, 140.1, 141.2, 150.9, 169.47, 169.49, 173.5; Anal. Calcd. for C22H22F2N2O6+0.22H2O: C, 58.41; H, 5.00; N, 6.19; Found: C, 58.06; H, 4.92; N, 5.90.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.ClCC1(Cl)C=CC(OCC2C=CC=CC=2)=C(Cl)C1.O[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.Cl[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][C:47]=1[Cl:53].ClCC1(C(F)(F)F)C=CC(OCC2C=CC=CC=2)=CC1>>[Cl:53][C:47]1[CH:48]=[C:49]([Cl:52])[CH:50]=[CH:51][C:46]=1[CH2:45][O:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][S:15][C:12]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]3[C:11]=2[CH2:10][CH2:9][CH2:8]3)=[CH:38][CH:39]=1
Reactant: OCc1ccc(O)cc1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: ClCC1(Cl)C=CC(OCc2ccccc2)=C(Cl)C1
Agent: FC(F)(F)C1(CCl)C=CC(OCc2ccccc2)=CC1
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(Cl)cc3Cl)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-chloromethyl-(2,4-dichloro-benzyloxy-benzene) prepared from 4-hydroxymethyl-phenol and 1-chloromethyl-2,4-dichloro-benzene in the manner analagous to Examples 14A and 14B. MS m/z 503 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][C:44](Cl)=[O:45]>>[CH2:34]([N:33]([CH2:36][CH3:37])[CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:44](=[O:45])[CH2:43][C:39]5[S:38][CH:42]=[CH:41][CH:40]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1)[CH3:35]
Reactant: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: CCN(CC)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 49 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[2-(diethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 49% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=7.2 Hz, 6H) 3.2 (s, 4H) 3.5 (s, 2H) 3.9 (s, 2H) 4.3 (s, 2H) 6.5 (d, J=5.3 Hz, 1H) 6.6 (s, 1H) 7.0 (m, 2H) 7.1 (d, J=1.5 Hz, 1H) 7.3 (d, J=5.1 Hz, 1H) 7.4 (m, 2H) 7.5 (m, 1H) 7.6 (s, 1H) 7.7 (s, 1H) 7.9 (s, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.6 (s, 2H) 10.4 (s, 1H). ES-LC/MS m/z 618 [M+H]+.
Reaction SMILES: C(O)=O.C1(C)C=CC=CC=1.C1CO[C:13]2([CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[C:21]([F:30])[CH:20]=3)[CH2:15][CH2:14]2)[O:12]1>O>[F:25][C:23]1[CH:24]=[C:19]([CH:16]2[CH2:17][CH2:18][C:13](=[O:12])[CH2:14][CH2:15]2)[CH:20]=[C:21]([F:30])[C:22]=1[C:26]([F:28])([F:29])[F:27]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1C(F)(F)F
Solvent: O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CCC(c2cc(F)c(C(F)(F)F)c(F)c2)CC1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Formic acid (11.3 g) and toluene (5 ml) were added to 1,1-ethylenedioxy-4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexane (15.7 g), followed by heating the mixture under reflux with stirring for 2 hours, adding the reaction solution to water (50 ml), extracting with ethyl acetate (100 ml), drying the organic layer over anhydrous MgSO4, and distilling off the solvent under reduced pressure, to obtain 4-(3',5'-difluoro-4'-trifluoromethylphenyl)cyclohexanone (12.0 g).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=2[F:39])=[CH:22][CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:39][C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][OH:18])=[N:25][C:24]=1[CH2:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2CC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
To a solution of 6-((tert-butyldiphenylsilyloxy)methyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (10.0 g) in THF (50 mL) was added a 1.0 M solution of tetrabutylammonium fluoride in THF (55.0 mL), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.00 g) as a white amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:18])=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:38])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:18])=[C:15]([Br:38])[C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2Cc3sc(C)cc3C2C1
Reactant: O=C1CCC(=O)N1Br
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2Cc3sc(C)c(Br)c3C2C1

Procedure:
A solution of the product from step c) (411 mg, 1.55 mmol) in AcOH (3.8 ml) and CHCl3 (3.8 ml) was treated with hydroquinone (5 mg) and NBS (331 mg, 1.86 mmol) at 40° C. for 3 hours in the dark. Next, the reaction mixture was carefully quenched with sat. NaHCO3 (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (MgSO4) and solvent evaporated in vacuo leaving the crude product that was purified by preparative TLC (hexanes:EtOAc-1:1) to give the subtitle compound. MS calculated for C14H18BrNO2S+H 344, observed 344, 346.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].[CH:18]1([N:22]2[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.ClCCl.CO.N>C1COCC1>[CH:18]1([N:22]2[CH2:27][CH2:26][CH:25]([O:17][C:14]3[CH:15]=[CH:16][C:11]([C:5]4([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]4)=[CH:12][CH:13]=3)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCN(C2CCC2)CC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Yield: 10.6 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.75 g, 3.19 mmol), 1-cyclobutylpiperidin-4-ol (0.45 g, 2.90 mmol), PPh3 (0.84 g, 3.19 mmol), THF (10 ml) and DIAD (0.66 ml, 3.19 mmol) were reacted together similarly to general procedure C. The crude material was subjected to chromatography on silica gel eluting with dichloromethane:methanol:ammonia (98:2:0.2) to provide the title compound (114 mg, 11%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ 1.71-1.77 (m, 4H), 1.85-1.90 (m, 4H), 1.94 (s, 6H), 1.99-2.06 (m, 4H), 2.12-2.16 (m, 2H), 2.20-2.28 (m, 2H), 2.45 (s, 2H), 2.58-2.70 (m, 2H), 2.79 (m, 1H), 3.46-3.53 (m, 2H), 3.72-3.75 (m, 2H), 4.39 (m, 1H), 6.91 (d, 2H), 7.26 (d, 2H). HRMS ESI+ m/z 373.2846 [MH]+.
Reaction SMILES: [CH2:1]([Li])CCC.CNCCN(C)C.[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>CCCCCC.O1CCCC1>[CH3:1][C:21]1[O:22][CH:23]=[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]=1[CH:24]=[O:25]
Reactant: [Li]CCCC
Reactant: O=Cc1cocc1-c1ccccc1
Agent: CNCCN(C)C
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1occ(-c2ccccc2)c1C=O
Reaction time: 0.5 h

Procedure:
n-Butyllithium (a 1.6 m solution in hexane, 2.43 ml, 3.89 mmol) was added to a solution of trimethylethylenediamine (397 mg, 3.89 mmol) in tetrahydrofuran (25 ml) at 0 degrees under argon. After 20 minutes the solution was cooled to-78 degrees and 4-phenyl-3-furaldehyde (Compound 54, 608 mg, 3.35 mmol) was added. This mixture was allowed to gradually warm to-20 degrees and stirred for 1 1/2 hours, then recooled to-78 degrees before n-butyllithium (a 1.6 M solution in hexane, 2.43 ml, 3.89 mmol) was added dropwise. The stirring mixture was again gradually warmed to-20 degrees and stirred for 2 hours before iodomethane (2.56 g 17.67 mmol) was added. After stirring for 18 hours at-20 degrees the reaction was quenched with ice-cold 10% (v/v) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 20% ethyl ether/hexanes to give the title aldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[NH:14][C:13]2=O)=[C:4]([F:25])[CH:3]=1.P(Cl)(Cl)([Cl:28])=O>N1C=CC=CC=1>[Cl:28][C:13]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:25])[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine within 15 minutes at 20°-40° C. and thereafter for 1 hour at 70° C. there is obtained 2-chloro-1-(4-chloro-2-fluoro -5-isopropoxyphenyl)-5-fluoro-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 60 MHz): 7.42 ppm (d,1H), 6.84 ppm (d,1H), 4.50 ppm (m,1H), 1.44 ppm (d,6H);
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23].N([O-])=O.[Na+].C(O)(=O)C.[ClH:32]>O.Cl[Cu]>[Cl:32][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]([F:18])([F:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([F:20])[C:3]=1[CH2:21][CH2:22][OH:23]
Reactant: Cl
Reactant: Nc1ccc(NC(=O)C(F)(F)c2ccccc2)c(F)c1CCO
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1ccc(Cl)c(CCO)c1F)C(F)(F)c1ccccc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A suspension of N-[4-amino-2-fluoro-3-(2-hydroxyethyl)phenyl]-2,2-difluoro-2-phenylacetamide (1.63 g, 5.00 mmol), as prepared according to the procedure of the preceding step, in 6N HCl (9 mL) was cooled in an ice-bath, and then a solution of NaNO2 (434 mg, 6.30 mmol) in H2O (2.4 mL) was added over a period of 5 minutes. After 30 minutes, acetic acid (2.9 mL) and concentrated HCl (2.9 mL) were added and the reaction mixture stirred for 1 hour. To this mixture was added a solution of CuCl (848 mg, 8.55 mmol) in concentrated HCl (5 mL) over a period of 20 minutes. After stirring in an ice-bath for 3 hours, the reaction mixture was extracted with EtOAc (200 mL×3). The extracts were combined, washed with H2O (2 times) and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to deliver the title compound (0.845 g, 48% yield) as a pale orange oil. 1H-NMR (400 MHz, CDCl3)δ 8.31 (s, 1H), 8.14 (t, J=8.6 Hz, 1H), 7.68-7.66 (m, 2H), 7.54-7.46 (m, 3H), 7.19 (dd, J=8.9, 1.7 Hz, 1H), 3.86 (dd, J=12.6, 6.5 Hz., 2H), 3.09 (dt, J=6.7, 2.3 Hz, 2H), 1.58 (t, J=5.7 Hz, 1H). Mass spectrum (LCMS, ESI) calc'd for C16H14ClF3NO2 (M+H): 344.1. Found: 344.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH:35]=O)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>O>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:34][CH2:35][N:11]2[CH2:10][CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[CH2:13][CH2:12]2)[CH2:23][N:24]([CH3:33])[C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: Oc1ccccc1C1CCNCC1
Solvent: O
Product: CN(C[C@@H](CCN1CCC(c2ccccc2O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: Cl

Procedure:
Using a procedure similar to that described in Example 1 (alternative preparation), except using 4-(2-hydroxyphenyl)piperidine and (S)-N-[2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide, the title compound was prepared. Chromatography, eluting with dichloromethane:methanol, followed by conversion to the hydrochloride salt gave a white solid; mp 205°-210° C.; MS: 511; NMR (CD3OD): 1.7-2.3 (m, 6), 2.7 (s, 1), 2.8-3.1 (m, 6), 3.2-3.8 (m, 5), 6.7-6.8 (m, 2), 7.0 (t, J=7, 3), 7.2 (br, 2), 7.4 (br, 2), 7.4 (br, 4), 7.5-7.7 (m, 2), 9.5 (s, 10), 10.5 (s, 1). Analysis for C29H32Cl2N2O2 ·1.0 HCl·0.75 H2O: Calculated: C, 62.04; H, 6.19; N, 4.99; Found: C, 62.24; H, 6.15; N, 5.08.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([NH:8][CH2:10][CH2:9][N:29]2[CH2:28][CH2:27][C:26]3([N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][NH:24][C:25]3=[O:32])[CH2:31][CH2:30]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 12 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 8.8 parts of methanol and 56 parts of benzene is stirred first for 1.50 hours at reflux and further overnight at room temperature. The reaction mixture is evaporated. The residue is dissolved in trichloromethane and the solution is washed with water. Then there are added 8 parts of methanol and silica gel and the whole is stirred for 10 minutes. The silica gel is filtered off and the filtrate is evaporated. The residue is stirred in 2,2'-oxybispropane. The product is filtered off and crystallized from 4-methyl-2-pentanone. It is filtered off and dried, yielding 13 parts of 4-fluoro-2-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro-[4,5]dec-8-yl)ethyl]benzamide; mp. 160° C.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:12](O)(=[O:16])[C:13]([CH3:15])=O.Cl>C(O)(=O)C>[CH2:1]([CH:5]1[CH:6]=[C:7]2[O:11][C:12](=[O:16])[C:13]([CH3:15])=[C:8]2[CH2:9][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1CCCC(=O)C1
Reactant: CC(=O)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC1=C2CCC(CC(C)C)C=C2OC1=O

Procedure:
The process according to claim 1, wherein 3-isobutyl-cyclohexanone and pyruvic acid are heated in an HCl and acetic acid solution to give 6-isobutyl-3-methyl-2,4,5,6-tetrahydro-benzo[b]-furan-2-one and this product is heated for 4 to 5 hours with pyridine hydrochloride to give p-isobutylhydratropic acid.