Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)=[CH:4][CH:3]=1.Cl[CH2:35][C:36](N(C)C)=[O:37]>>[C:36]([N:29]1[CH2:28][CH2:27][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=3)[CH:15]=4)[CH:17]=2)[CH2:31][CH2:30]1)(=[O:37])[CH3:35]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccc(F)cc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 55 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(4-fluorobenzyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 30 mg (55%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1 H) 7.81 (s, 1 H) 7.77 (d, 1 H) 7.62 (d, 1 H) 7.32-7.40 (m, 2 H) 7.19 (d, 1 H) 7.03-7.10 (m, 2 H) 6.55 (s, 1 H) 5.61 (s, 2 H) 4.63 (d, 1 H) 4.00 (d, 1 H) 3.45 (tt, 1 H) 3.25 (td, 1 H) 2.75 (td, 1 H) 2.07-2.18 (m, 5 H) 1.62-1.72 (m, 2 H).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([Cl:30])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:23]=[CH:22][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([Cl:30])[S:27][C:17]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH2:10]2)=[C:4]([CH3:25])[CH:3]=1.Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)[C:30]([Cl:40])=[CH:29][N:28]=1.Cl.C([O-])(O)=O.[Na+]>CC(O)C>[Cl:40][C:30]1[C:31]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)=[N:32][C:27]([NH:1][C:2]2[C:7]([CH3:8])=[CH:6][C:5]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:11](=[O:24])[CH2:10]3)=[C:4]([CH3:25])[CH:3]=2)=[N:28][CH:29]=1
Reactant: COc1ccc(CN2CCC(c3cc(C)c(N)cc3C)CC2=O)cc1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(CN2CCC(c3cc(C)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2=O)cc1
Temperature: 130 °C

Procedure:
To a mixture of 4-(4-amino-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one (23 mg, 0.094 mmol) and 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (29 mg, 0.086 mmol) in iPrOH (1 mL) was added HCl (60 uL, 4N in dioxane). The reaction vessel was then sealed and heated to 130° C. for 4 hr. After cooling to room temperature, the mixture was treated with saturated NaHCO3 aqueous solution (3 mL) and extracted with EtOAc (3×4 mL). The organic layers were combined and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0˜10% MeOH/CH2Cl2) to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one. ESMS m/z 546.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[C:22](F)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)CC)C>C(O)(C)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:28])[F:29])=[CH:24][N:23]=3)[CH2:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(c3ncc(C(F)(F)F)cc3Cl)C2)no1
Temperature: 175 °C
Reaction time: 8 h

Procedure:
A microwave reaction vial is charged with piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (94 mg; 0.327 mmol), 3-chloro-2-fluoro-5-trifluoromethylpyridine (0.043 mL; 0.33 mmol), triethylamine (0.092 mL; 0.66 mmol) and t-butanol (0.5 mL). The vial is heated in microwave at 175° C. for 1 hour then left standing at room temperature overnight. The reaction mixture is concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride then recrystallization from hot methanol provides the title compound, m/z 431 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:30](Cl)(Cl)=[O:31].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:27][CH:26]=[C:25]([O:28][CH3:29])[CH:24]=3)[NH:1][C:30]2=[O:31])[CH2:10][CH2:11]1
Reactant: COc1ccc(N)c(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(=O)n(CCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c(=O)c2c1

Procedure:
The product of step (i) above was dissolved in toluene (10 ml). A solution of phosgene 2.0 M in toluene (10 ml) was added, the solution heated under reflux for 1 hour and cooled. Ethyl acetate and aqueous NaHCO3 solution were added, the organic phase separated, dried and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol, 95:5). The titled product was obtained as a solid (0.11 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@@H:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1O)[CH:27]=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:20][C@@H:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[N:14]=1)[CH2:16][CH2:17][CH2:18][CH3:19])[CH:27]=[O:28]
Reactant: CCCC[C@H](O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reactant: O=Cc1ccc(O)c(Cl)c1
Product: CCCC[C@@H](Oc1ccc(C=O)cc1Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Yield: 19.5 %

Procedure:
Prepared according to the procedure used to prepare Intermediate 103 starting from (1S)-1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-pentanol (196 mg, 0.63 mmol) and 3-chloro-4-hydroxybenzaldehyde (141, 0.90 mmol) to afford the title compound (55 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5](=[CH:10][CH:11]=1)[C:6](OC)=[O:7].O.[NH2:14][NH2:15]>CO>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:14][NH2:15])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)cc1O
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(F)cc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-fluorosalicylate (500 mg, 2.94 mmol, commercially available from e.g. Apollo, Alfa Aesar or ABCR) in methanol (15 ml) stirred under argon at room temp was added neat hydrazine monohydrate (0.722 ml, 14.69 mmol). The reaction mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate (˜50 ml) and water (˜25 ml). The aqueous phase was extracted with ethyl acetate (2×25 ml) and the combined organic extracts washed with brine (25 ml), dried over sodium sulphate, evaporated in vacuo and dried (vacuum oven, 40° C., 24 hr) to afford the crude product as an off-white solid in 385 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CCCCCC>[CH3:14][N:15]([CH3:17])[CH:16]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: COC(OC)N(C)C
Solvent: CCCCCC
Product: CC(=O)C(=CN(C)C)c1ccc(F)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-propanone (10.0 g) and N,N-dimethylformamide dimethylacetal (8.00 g) was stirred at 120° C. for 2 hrs. The reaction mixture was cooled, and hexane was added to the precipitated solids, which were collected by filtration to give 4-(dimethylamino)-3-(4-fluorophenyl)but-3-en-2-one (11.3 g, yield 83%) as a pale-yellow solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2([CH2:16][C:15](=O)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]4[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=4)[C:21]#[N:22])[CH:13]=3)[O:8]2)[CH2:4][O:3]1.C[Si]([N:31]=[C:32]=[N:33][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:21]([C:20]1[CH:19]=[C:18]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][C:5]([CH2:6][OH:7])([CH2:4][OH:3])[CH2:16]/[C:15]/3=[N:33]\[C:32]#[N:31])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: CC1(C)OCC2(CO1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\CC(CO)(CO)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
To a solution of 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile (155 mg, 0.44 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.88 mL, 0.88 mmol) dropwise within 15 min at room temperature. The mixture was stirred for 1 h after the addition. To this mixture was added bis-trimethylsilylcarbodiimide (181 mg, 217 μL 0.97 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (25 g), stirred for 30 min and filtered through a pad of Celite. The separated aqueous phase of the filtrate was extracted with DCM once. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2,2-bis(hydroxymethyl)chroman-4-ylidene)cyanamide (160 mg), which was used in the next step without further purification. MS ESI +ve m/z 374 (M+H)+.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.Cl>ClCCl>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([C:18]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22](=[O:23])[C:11]3[CH:12]=[CH:13][C:8]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)[CH:20]=2)=[O:28])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)c2ccc(Oc3ccccc3)cc2)c1
Temperature: -60 °C
Reaction time: 72 h
Yield: 60.8 %

Procedure:
Diphenyl oxide (51 g), 100 ml of dichloromethane and 13.3 g of aluminum trichloride are placed in a flask equipped with a mechanical stirrer, a reflux condenser and an addition funnel. After cooling the flask to -60° C., 10.15 g of isophthaloyl chloride is added over a 30-minute period. The reaction is stirred at 25° C. for 72 hours and refluxed for 4 hours. The reaction mixture is poured into 100 ml of 1M hydrochloric acid and the organic layer is washed once with ammonium hydroxide and twice with water. The organic layer is dried with sodium bisulfate and the solvent is evaporated. The product is recrystallized from methylethyl ketone, yielding 14.3 g (61 percent yield) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7](N)=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[ClH:22]>CN(C)C=O>[C:12]1([O:11][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=2[Cl:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1Oc1ccccc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(Oc2ccccc2)c1
Yield: 60 %

Procedure:
4-Nitro-2-phenoxyaniline was dissolved in N,N-dimethylformamide and hydrochloric acid and diazotized with sodium nitrite. The resulting slurry was added to a solution of cuprous chloride in hydrochloric acid to give a 60-70% yield of 2-chloro-5-nitrophenyl phenyl ether, b2-3 180°-90°, m. 73°-5°. This was converted to N-(4-nitro-2-phenoxyphenyl)-pyrrolidine, m. ca. 90°, by refluxing with excess pyrrolidine in 94-97% yield. Catalytic reduction followed by treatment with hydrochloric acid then gave N-(4-amino-2-phenoxyphenyl)pyrrolidine hydrochloride, which was slurried with water and diazotized conventionally with sodium nitrite. The clarified diazonium chloride solution was finally treated with hexafluoroarsenic acid to precipitate the desired 3-phenoxy-4-(1-pyrrolidinyl)benzenediazonium hexafluoroarsenate, m. 138°-140° (dec.), E395 36,3000) in 96% of the yield calculated from the amount of N-(4-nitro-2-phenoxyphenyl)pyrrolidine charged to the catalytic reduction preceding the diazotization.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[NH:3]1.P(Br)(Br)([Br:18])=O>O>[Br:18][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Solvent: O
Product: COC(=O)c1ccc(C(F)(F)F)nc1Br
Temperature: 25 °C
Yield: 13.4 %

Procedure:
A suspension of 22.0 g (0.100 mol) of the product from Example 1 and 28.7 g (0.100 mol) of phosphorous oxybromide was heated at 75°-120° C. over 45 minutes utilizing an oil bath as the heat source. The reaction was also connected to a water scrubber to trap the gas by-products. The mixture was then cooled to room temperature, diluted with water and extracted with methylene chloride. The combined organic layers were washed with saturated sodium bicarbonate solution, washed with brine, dried over magnesium sulfate and evaporated to an oil which was purified by flesh chromatography utilizing 20% ethyl acetate/petroleum ether as the eluent to afford 3.8 g (13.3%) of an oil. 1H NMR (CDCl3) δ4.0 (3H, s), 7.72 (1H, d, J=8 Hz), 8.2 (1H, d, J=8 Hz); IR (neat) 1740, 1590, 1455, 1335, 1275, 1140, 1100, 1050 cm-1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:11][CH2:10][CH:9]2[O:12][CH:8]2[CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21].[OH-].[Na+]>C(#N)C>[OH:12][C@H:8]1[C@H:9]([O:21][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:14]=2[CH3:13])[CH2:10][CH2:11][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]1
Reactant: Cc1cccc(O)c1C
Reactant: CS(=O)(=O)N1CCC2OC2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cccc(O[C@@H]2CCN(S(C)(=O)=O)CC[C@H]2O)c1C
Temperature: 25 °C

Procedure:
7.0 g (0.036 mol) of 1-methanesulphonyl-hexahydro-4,5-epoxy-1H-azepine are dissolved, together with 8.9 g (0.073 mol) of 2,3-dimethyl-phenol, with 36.6 ml of 2 N sodium hydroxide solution (0.013 mol) in 200 ml of acetonitrile. The reaction mixture is heated under reflux for 5 days, then cooled to room temperature and concentrated under a water pump vacuum. The residue is then dissolved in 200 ml of methylene chloride and the organic phase is washed with three times 100 ml of 2 N sodium hydroxide solution and then with water, dried over sodium sulphate and evaporated under a water pump vacuum. The resulting crude product is purified by preparative thick layer chromatography (100×20 cm silica gel plates, layer thickness 1.5 mm). Crystalline trans-4-hydroxy-5-(2,3-dimethylphenoxy)-1-methanesulphonyl-hexahydro-1H-azepine with a melting point of 112°-115° is obtained by elution with a 3:1 mixture of toluene/ethyl acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=3)=[O:39])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)Nc3ccc(F)cc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
83 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.2 eq.) of 4-fluorophenyl isocyanate were reacted according to General Method 4. Yield: 44 mg (67% of theory)
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.FC(F)(F)C(O)=O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C:6]1[C:7]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=1[O:4][CH2:3][CH2:2][O:1][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2ccccc2OC)cc1
Reactant: C1=COCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1

Procedure:
A solution of 110 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p-vinylbenzenesulfonamide in 3 ml of absolute tetrahydrofuran was treated with 0.3 ml of 3,4-dihydro-2H-pyran and 4 drops of trifluoroacetic acid. After boiling under reflux overnight, the solvent was distilled under reduced pressure and the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (9:1). There were obtained 100 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide as a white resin, MS: 460 (M--SO2 +H); 430 (M--SO2 +OCH3).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=1>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=3)[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)cc1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=380.3 [M+H]+.
Reaction SMILES: C[O-].[Na+].[C:4]([C:6]1[CH:23]=[CH:22][C:9]2[N:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)[CH:11]=[N:12][C:8]=2[CH:7]=1)#[N:5].[C:24]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[C:4]([C:6]1[CH:23]=[CH:22][C:9]2[N:10]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1)#[N:5]
Reactant: O=C1CCCCC1
Reactant: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]ccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)ncn2-c1ccc2[nH]cc(C3=CCCCC3)c2c1

Procedure:
A solution of sodium methoxide (0.25 g, 4.6 mmol, 3 equivalents), 5-cyano-1-(indol-5-yl)benzimidazole (0.40 g, 1.54 mmol), and cyclohexanone (0.175 mL, 1.69 mmol, 1.1 equivalents) in N,N-dimethylformamide (8 mL) was heated at 130° C. under nitrogen for 12 hours. The solvent was removed by evaporation under reduced pressure, and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was separated, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue (0.16 g) using silica gel (approximately 5 g) and elution with ethyl acetate/hexanes [1:1] afforded the title compound. (19%) as a pale yellow solid. Rf =0.3 in ethyl acetate/hexanes [1:1]; 1H NMR (CDCl3) δ10.35 (br s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 7.80 (s, 1H), 7.45-7.43 (m, 3H), 7.21 (s, 1H), 7.07 (dd, J=8.5 and 1.9 Hz, 1H), 6.04 (br m, 1H), 2.32 (br m, 2H), 2.08 (br m, 2H), 1.72-1.60 (m, 2H), 1.60-1.50 (m, 2H); 13C NMR (CDCl3) δ145.7, 142.4, 137.5, 136.7, 130.9, 126.8, 125.7, 124.8, 123.8, 123.6. 122.5, 119.5, 119.2, 118.2, 117.2, 112.7, 112.1, 105.6, 28.4, 25.5, 22.9, 22.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(-n2cccn2)cc1
Product: C[C@@H](n1ncn(-c2ccc(-n3cccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1-pyrazolyl )phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 19).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:17][C:18](=O)[C:19]([CH3:22])([CH3:21])[CH3:20])[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[N+:6]=1[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:19]([C:18]1[N:1]=[C:2]2[N:3]([CH:17]=1)[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(C)CCC[n+]1c(N)n(CC(=O)C(C)(C)C)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCCn1c2ccccc2n2cc(C(C)(C)C)nc12
Yield: 90 %

Procedure:
Heat at reflux for 25 minutes 3 mmol of the hydrobromide obtained in Step A and 4 g of sodium carbonate in 25 ml of ethanol. Evaporate, treat the residue twice with 10 ml of chloroform each time, and pass the resulting chloroform solutions over a column of alumina. Evaporate the eluate. The title compound is obtained in the form of an oil.