Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].N.[C:3]([O:7][C:8](=[O:33])[N:9]([CH3:32])[C:10]12[CH2:15][CH:14]1[CH2:13][N:12](S(C1C=CC(C)=CC=1)(=O)=O)[CH:11]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:6])([CH3:5])[CH3:4].[Cl-].[NH4+]>C1COCC1>[C:3]([O:7][C:8](=[O:33])[N:9]([CH3:32])[C:10]12[CH2:15][CH:14]1[CH2:13][NH:12][CH:11]2[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3(N(C)C(=O)OC(C)(C)C)C2c2ccccc2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C12CC1CNC2c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a flame dried 125 mL rbf equipped with a dry ice condenser was added fresh sodium metal (0.32 g, 14.0 mmol). The flask was immersed in a −78° C. bath and ammonia gas was condensed into the flask until it was about a third full. The starting material methyl-[2-phenyl-3-(toluene-4-sulfonyl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acid tert-butyl ester (Intermediate 9) (0.62 g, 1.40 mmol) in THF (10 mL) was added to the flask in a thin constant stream and the mixture was stirred for 10 minutes at which point tlc indicated the reaction was complete. Solid ammonium chloride was added cautiously and the reaction warmed to room temperature. The volatile solvents were allowed to evaporate and the residue was partitioned between 1N NaOH and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give methyl-(2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-carbamic acid tert-butyl ester as an oil (0.40 g, quantitative yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][CH:12]=[O:13])[CH:2]=1.[CH:14](OC(=O)C)=[O:15].C(O)=O.C(OC(=O)C)(=O)C>C1COCC1.[Pt]=O.CO.C(O)(=O)C>[CH:14]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][CH:12]=[O:13])[CH2:2]1)=[O:15]
Reactant: CC(=O)OC=O
Reactant: O=CNc1cnc2ccccc2c1
Agent: O=[Pt]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNC1Cc2ccccc2N(C=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A mixture of N-(3-quinolyl)formamide (30.0 g, 0.175 mol), platinum oxide (2.0 g) and acetic acid (300 mL) was hydrogenated (50 lb. initial H2 pressure) until 2 equivalents of H2 were consumed (reaction time 3 hours). The mixture was filtered through celite and the acetic acid removed under pressure. It was dissolved in ethyl acetate and washed with NaOH solution and water. Evaporation of the ethyl acetate gave 29.4 g of crude material. This was dissolved in 200 mL THF and acetic formic anhydride (prepared from formic acid (27.2 g, 0.59 mol) and acetic anhydride (53.5 g, 0.52 mol) was added at 0° C. After 15 minutes, the solution was allowed to warm to room temperature, and after an additional 15 minutes, methanol (60 mL) was added. The solution was evaporated and the resulting oil was partitioned between ethyl acetate and 4N sodium hydroxide solution. The sodium hydroxide solution was repeatedly extracted with ethyl acetate. The combined ethyl acetate was evaporated, and the crude product was purified by chromatography on silica gel using 2.5% methanol:chloroform as eluant to give 22.55 g (69%) of product. An analytical sample was crystallized from methanol:ether (1:3); mp 125°-128° C. Anal. Calcd. for C11H12N2O2 : C, 64.69; H, 5.92; N, 13.72. Found: C, 64.60; H, 5.97; N, 13.66.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]([O:18][CH3:19])=[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:21][O:20][C:7]1[CH:8]=[C:9]([O:18][CH3:19])[C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[CH:11][C:6]=1[CH:2]=[O:1]
Reactant: COc1cc(OC)c(C2OCCO2)cc1-c1cnccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(-c2cnccn2)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
Ex-46D: 2-(5-[1,3]Dioxolan-2-yl-2,4-dimethoxy-phenyl)-pyrazine (1.02 g, 3.54 mmol) was dissolved in acetone and p-toluenesulfonic acid (100 mg, 0.53 mmol) and water (5 mL) were added. The solution was stirred for 3 h at room temperature, then concentrated on the rotavap. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was washed with 25% saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated. Drying gave 0.30 g of 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde as a yellow solid (18% yield). 1H-NMR (CDCl3) δ 10.35 (s, 1H), 9.06 (d, J=2 Hz, 1H), 8.63–8.65 (m, 1H), 8.45 (d, J=2 Hz, 1H), 8.39 (s, 1H), 6.56 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). HRMS m/z: calc. 244.0848, found 244.0853.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([O:7][C:8]([NH:10][C@H:11]([C:23]([NH:25][CH3:26])=S)[CH2:12][C:13](OCC1C=CC=CC=1)=[O:14])=[O:9])([CH3:6])[CH3:5]>C1COCC1.CCO>[CH3:26][N:25]1[C:13](=[O:14])[CH2:12][C@H:11]([NH:10][C:8](=[O:9])[O:7][C:4]([CH3:6])([CH3:5])[CH3:3])[CH2:23]1
Reactant: CNC(=S)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C[C@@H](NC(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.9 %

Procedure:
NaBH4 (2.7 g, 74.23 mmol) was added portionwise to an ice cold solution of phenylmethyl (3S)-3-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-(methylamino)-4-thioxobutanoate (3.3 g, 9.36 mmol) and NiCl2.6H2O (5.1 g, 21.62 mmol) in THF (50 mL) and EtOH (50 mL) and the reaction mixture was stirred at room temperature for 2.5 days. The resulted black mixture was then filtered through a pad of Celite and the filtrate was concentrated. To this residue was added toluene (15 mL) and the solution was refluxed for 12 h. After cooling to room temperature, the reaction was concentrated and purified via silica gel chromatography with 0% MeOH in CH2Cl2 grading to 10% MeOH in CH2Cl2 to give the titled product (0.96 g, 48%) as a white solid. 1H-NMR (CDCl3) δ: 1.466 (9H, s), 2.270 (1H, dd, J=16 Hz, 4 Hz), 2.770 (1H, m), 2.874 (3H, s), 3.260 (1H, dd, J=8 Hz, 4 Hz), 3.720 (1H, m), 4.310 (1H, s), 4.820 (1H, s). LC-MS (ES) m/e 215.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[C:9]1=[C:16]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:29])CBr.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([C:26]([O:25][CH3:24])=[O:29])[CH:10]([CH3:15])[CH:9]1[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CC1CN(C(=O)OC(C)(C)C)C(=C=O)C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1C(C)CN(C(=O)OC(C)(C)C)C(C)C1C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 3,5-dimethyl carbonyl piperazine-1-carboxylic acid t-butyl ester (18.7 g), potassium carbonate (14.5 g), bromo acetic acid methyl ester (14.7 g), DMF (90 mL) was stirred at 60° C. for 3 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound. This compound was provided to the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH2:27])[CH:10]=1.[CH3:34][N:35]([CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1)[C:36]([C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][CH:46]=1)[C:41](O)=[O:42])=[O:37].CCN=C=NCCCN(C)C.[ClH:66]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[ClH:66].[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[C:38]([C:36]([N:35]([CH3:34])[CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][O:52][CH2:53][CH2:54]3)=[O:37])[CH:39]=2)[CH:10]=1)=[O:28]
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(piperidin-1-yl)phenyl)isonicotinamide (1 g, 2.09 mmol, 1.00 equiv, 95%) in dichloromethane (30 mL), 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (960 mg, 3.12 mmol, 1.50 equiv, 95%), EDC.HCl (840 mg, 4.38 mmol, 2.00 equiv), and 4-dimethylaminopyridine (540 mg, 4.43 mmol, 2.00 equiv). The resulting solution was stirred for 3 h at 25° C. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of NH4Cl (aq), 1×30 mL of 10% sodium bicarbonate, and 1×30 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate:methanol (20:1). This resulted in 1.30 g of N1-(2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide as a brown oil. The brown oil was dissolved in 40 mL of methanol. HCl gas was added at 0° C. The mixture was stirred for 20 min at 0° C. The mixture was concentrated under vacuum. The product was obtained as 1.40 g (86%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6+D2O, ppm): δ 9.96 (m, 1H), 8.94 (d, J=6 Hz, 1H), 8.59 (m, 2H), 8.49 (s, 1H), 7.93-8.07 (m, 2H), 7.87-8.03 (m, 2H), 7.54-7.80 (m, 7H), 4.59 (s, 2H), 4.12 (m, 1H), 3.99-4.03 (m, 2H), 3.88 (m, 2H), 3.76-3.79 (m, 2H), 3.58 (m, 2H), 3.43 (m, 2H), 3.15-3.17 (m, 3H), 2.96 (s, 3H), 1.97 (m, 4H), 1.71 (m, 2H). MS (ES, m/z): 729 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(O)CCO.[CH3:27][N:28](C)[CH:29]=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:28]([CH3:29])[CH3:27])[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Clc1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1
Solvent: OCCCO
Product: CN(C)c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1

Procedure:
300 mg (0.95 mmol) of N-(3-chloro-phenyl)-4-(2-chloro-4-pyridyl)-2-pyrimidineamine (see Example 1), 5.3 ml of 1,3-propanediol and 3.0 ml of dimethylformamide are stirred for 43 hours at 105°. After concentration and repeated chromatography (methylene chloride:methanol=98:2) N-(3-chloro-phenyl)-4-(2-dimethylamino-4-pyridyl)-2-pyrimidineamine is obtained; m.p. 176°-178°, FAB-MS: 326 (M+ +H).
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(N(CC)CC)C>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: Oc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCC1=C(C)C(Oc2ccccc2)CC1=O
Reaction time: 4 h

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), phenol (6 parts) and triethylamine (1/5 part) were charged and stirred at a temperature of 50° to 80° C. for 4 hours. The reaction mixture was treated in the same manner as in Example 25 to obtain 2-allyl-3-methyl-4-phenoxy-2-cyclopentenone. Yield, 95%. nD20 1.5539.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[N:16][C:15]=1Cl)=[O:13]>C(O)(=O)C>[Cl:20][C:18]1[N:17]=[N:16][C:15]2[NH:1][C:2]3[C:7]([C:8]([NH2:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=3[NH:11][C:12](=[O:13])[C:14]=2[CH:19]=1
Reactant: NC(=O)c1cccc(NC(=O)c2cc(Cl)nnc2Cl)c1N
Solvent: CC(=O)O
Product: NC(=O)c1cccc2c1Nc1nnc(Cl)cc1C(=O)N2
Yield: 51.2 %

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (2-amino-3-carbamoyl-phenyl)-amide (500 mg, 1.53 mmol) in acetic acid (AcOH) (25 ml) was heated at 100° C. for 1 h. The cooled solution was concentrated and partitioned between EtOAc and saturated Na—HCO3, the organic layer separated, dried, filtered and concentrated to give the product as a brown solid (227 mg, 51%).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH:16][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Nc1cc(F)ccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylacetyl chloride (4.2 mL, 34.1 mL) was fast dropwise added to a solution of 2-bromo-5-fluorobenzenamine (4.31 g, 22.7 mmol) in CH2Cl2 (50 mL) at room temperature, followed by the addition of DIEA (7.9 mL, 45.4 mmol). The resulting mixture was stirred at room temperature for 2 hrs, and then partitioned between HCl (1N, 200 mL) and EtOAc (250 mL). After separation, the organic phase was washed with brine (50 mL), dried on MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 20˜40% EtOAc/hexanes (1200 mL) to afford the expected product, as a colorless oil (6.07 g, 98% yield); 1H NMR (400 MHz, CDCl3) δ ppm 1.33 (s, 9 H), 6.69 (ddd, J=8.81, 7.55, 3.02 Hz, 1 H), 7.45 (dd, J=8.81, 5.79 Hz, 1 H), 8.04 (s, 1 H), 8.28 (dd, J=11.08, 3.02 Hz, 1 H); Mass spec. 274.04 (MH+), Calc. for C11H13BrFNO 273.02
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][CH:14]=1
Reactant: COc1cc2nccc(Oc3ccc(OCC(=O)Nc4ccccc4C)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(OCCNc4ccccc4C)cc3)c2cc1OC
Yield: 46.1 %

Procedure:
N1-(2-Methylphenyl)-2-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenoxy}acetamide (65 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A borane-tetrahydrofuran complex (1.0 M solution: 0.74 ml) was then added to the solution, and the mixture was heated under reflux overnight. 1 N Hydrochloric acid was added thereto, and the mixture was further heated under reflux for 30 min. A 5% aqueous sodium hydroxide solution was added to the reaction solution, the mixture was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (29 mg, yield 46%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=O.N1C=CC=CC=1.Cl.[O:21]([NH2:23])[CH3:22]>O>[CH3:22][O:21][N:23]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH3:13])=[C:2]([OH:1])[CH:3]=1
Reactant: CON
Reactant: CCCOc1ccc(C=O)cc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCOc1ccc(C=NOC)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 120.9 %

Procedure:
An amount of 3-hydroxy-4-propoxybenzaldehyde (150 mg, 0.83 mmol) is added pyridine (4.0 ml) at room temperature, followed by addition of methoxylamine hydrogen chloride (101.2 mg, 1.2 mmol). The mixture is stirred at ambient temperature for 24 h, and 4 mL of water is added. After the solvents were evaporated, the residue is dissolved 8 mL of anhydrous ether, washed successively with 2 mL of aqueous sodium bicarbonate, 2 mL of sodium bisulfite, and 2 mL of brine. Dried over magnesium sulfate, evaporated to give a yellow solid (210 mg). MS (ESI) m/z 210.5 (M+1)
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:33]([NH:36][C:37]([CH3:41])([CH3:40])[CH2:38][OH:39])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[OH:39][CH2:38][C:37]([NH:36][S:33]([C:29]1[CH:28]=[C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Orange solid. MS (ISP) 582.0 [(M−H−]; mp 232° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)[CH2:4][CH3:5].S(C1C=CC(C)=CC=1)(O[CH2:15][C@@H:16]1[CH2:30][C@H:29]2[C@@H:19]([CH2:20][C:21]3[C:31]4[C:24](=[CH:25][CH:26]=[CH:27][C:28]2=4)[NH:23][CH:22]=3)[N:18]([CH3:32])[CH2:17]1)(=O)=O>CN(C)C=O>[CH3:32][N:18]1[C@H:19]2[C@@H:29]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:31]=3[C:21]([CH2:20]2)=[CH:22][NH:23]4)[CH2:30][C@@H:16]([CH2:15][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH2:3][CH2:4][CH3:5])[CH2:17]1
Reactant: CCCc1ncc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nccn1C[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
0.68 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.1 g of 2-propylimidazole and 50 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (eluted with ethyl acetate:benzene=1:2, and then with ethyl acetate). The resulting product was recrystallized from acetone-hexane to obtain 0.8 g of the titled compound as colorless needles having a melting point of 223°-227° C. (with decomposition).
Reaction SMILES: Br.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[NH:15].[CH3:16][C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:2][O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[S:8][C:7]1=[N:15][C:22]([CH:18]1[C:19]([CH3:21])([CH3:20])[C:17]1([CH3:25])[CH3:16])=[O:23]
Reactant: COCCn1c2c(sc1=N)CCCC2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCn1c2c(sc1=NC(=O)C1C(C)(C)C1(C)C)CCCC2

Procedure:
A mixture of the product of Example 121A (156 mg, 0.55 mmol), 2,2,3,3-tetramethylcyclopropanecarboxylic acid (94 mg, 0.66 mmol), HATU (479 mg, 0.83 mmol) and triethylamine (0.46 mL, 3.30 mmol) in 10 mL of DMF was processed according to the method of Example 2B to provide the title compound: 1H NMR (500 MHz, DMSO-d6) δ 1.16 (s, 6H) 1.23 (s, 6H) 1.45 (s, 1H) 1.69-1.82 (m, 4H) 2.43-2.48 (m, 2H) 2.54-2.59 (m, 2H) 3.24 (s, 3H) 3.60 (t, J=5.3 Hz, 2H) 4.16 (t, J=5.3 Hz, 2H); MS (DCI/NH3) m/z 337 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][N:2]([CH3:18])[CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)C(=O)[C@@H]1CCCN1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCCN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
N,N-Dimethyl-1-(phenylcarbonyl)-L-prolinamide (4.50 g, 18.269 mmol) was dissolved in 100 mL of THF, cooled to 0° C., and then LiAlH4 (1.386 mg, 36.54 mmol) was added portion wise. The mixture was heated to 80° C. for 2 h, then allowed to cool to RT. The reaction was quenched in succession with H2O (1.5 mL), 15% aq. NaOH (1.5 mL) and H2O (4.5 mL) and was stirred at room temperature overnight. The contents were filtered, and the filtrate was concentrated in vacuo to provide N,N-dimethyl-1-[(2S)-1-(phenylmethyl)-2-pyrrolidinyl]methanamine (3.7305 g, 94%). LCMS: (M+H)+: 219.1.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:5]=2[N:6]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: COc1ccc2nc(Cl)[nH]c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(Cl)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 159.1 %

Procedure:
2-Chloro-5-methoxybenzimidazole (0.3 g, 1.64 mmol) was suspended in dichloromethane (20 ml) under argon followed by the addition of boron tribromide (233 ul, 2.46 mmol). The reaction mixture was stirred for 2 hours at ambient temperature. The solvent was evaporated and the resulting powder was added in portions to methanol (30 ml). Silica was added and the solvent was evaporated. The resulting powder was placed on the top of a silica column and the product was eluted off using dichloromethane/methanol (95/5). Evaporation of the solvent and trituration in ether gave 2-chloro-5-hydroxybenzimidazole (440 mg, 99%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:27]([C:28]([NH2:30])=O)=[C:26]([CH3:31])[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:24](=[O:42])[NH:23]1)(=[O:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][CH2:10][S:11]([C:14]1[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=1[CH:22]1[C:27]([C:28]#[N:30])=[C:26]([CH3:31])[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[C:24](=[O:42])[NH:23]1)(=[O:13])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2S(=O)(=O)CCO[Si](C)(C)C(C)(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(=O)(=O)CCO[Si](C)(C)C(C)(C)C)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
The reaction was carried out under argon. (rac)-4-{2-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]-4-cyanophenyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (740 mg, 1.18 mmol) was initially charged in dry THF (30 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 1.699 g, 7.13 mmol; 6 eq.) was added and the mixture was stirred at RT. After 75 min, HPLC control showed complete conversion. The reaction mixture was then taken up in ethyl acetate (150 ml). The organic phase was washed with saturated sodium chloride solution (3×50 ml), dried over solid sodium sulfate, filtered and concentrated. The residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 1:1). The title compound was obtained as a colorless solid (550 mg, 77% of theory).