Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[CH:11]([O:22]CC1C=CC(OC)=CC=1)[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:33])([CH3:32])[CH:11]([OH:22])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(COC(C(=O)OCc2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(COS(=O)(=O)CCCCl)C(O)C(=O)OCc1ccccc1
Yield: 66 %

Procedure:
Following the general procedure for the oxidative cleavage of (4-methoxy)benzyl ethers of Description 19 phenylmethyl (2R/S)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethyl-butanoate (32a) (0.22 g, 0.4 mmol) dissolved in a mixture of dichloromethane (DCM) and water (10:1) (3 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (200 mg, 0.87 mmol). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 100 mg (60% yield) of the title compound (32b) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=0.95 (s, 3H), 1.08 (s, 3H), 2.27-2.34 (m, 2H), 3.04 (d, J=6.0 Hz, 1H), 3.26-3.29 (m, 2H), 3.65-3.69 (m, 2H), 3.97 (d, J=8.8 Hz, 1H), 4.08 (d, J=5.6 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 5.24 (d, J=12.4 Hz, 1H), 5.28 (d, J=12.4 Hz, 1H), 7.36-7.38 (m, 5H) ppm. MS (ESI) m/z: 379.03 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:13]([CH3:14])=[C:12](O)[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:3][C:4]1[C:13]([CH3:14])=[C:12]([C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:11]2[C:6](=[C:7]([F:20])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=2)[N:5]=1
Reactant: CCCC(=O)Cl
Reactant: Cc1nc2c(F)cc(C(C)(C)C)cc2c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)c1c(C)c(C)nc2c(F)cc(C(C)(C)C)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In tetrahydrofuran (3 ml) was suspended 60% sodium hydride (20 mg). The compound 1 (124 mg) was added to the suspension under ice cooling, and the mixture was stirred for 30 min. Further, butyryl chloride (200 μl) was added thereto, and the mixture was stirred for 3 hr. The reaction solution thus obtained was poured into ice water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed under the reduced pressure. The crude product was purified by chromatography on silica gel (Wako Gel C-200, elution solvent: n-hexane-ethyl acetate (3:1)) to give 2,3-dimethyl-6-t-butyl-8-fluoro-4-butyrylquinoline (compound 4, 64 mg). 1H-NMR data on this compound in deutro-chloroform were as shown below.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]=[CH2:24]>C(#N)C>[CH2:24]([N:11]1[CH2:12][CH2:13][C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])([OH:14])[CH2:10]1)[CH:23]=[CH2:22]
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 8: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol) and 3-bromo-1-propene (0.23 mL, 2.78 mmol). Refluxed for 2 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 5:1). Yield: 0.33 g. [α]D=−26.6° (methanol). The amine was converted to the oxalic acid salt and recrystallized from methanol/diisopropyl ether: M.p. 120° C.; MS m/z (relative intensity, 70 eV) (239 (M+, 25), 198 (48), 141 (35), 127 (23), 83 (bp).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:12][C:7]=2[O:6][C:5]1=[O:19].C(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:10]1[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: BrBr
Reactant: CC1C(=O)Oc2cc(N3CCOCC3)ccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1C(=O)Oc2cc(N3CCOCC3)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 11 g (0.069 mole) of bromine in 50 ml of chloroform is added dropwise in the course of one hour, at from 0° to 5° C. while stirring, to a mixture of 15 g (0.064 mole) of 3-methyl-6-morpholinobenzofuran-2(3H)-one in 120 ml of chloroform. Subsequently the mixture is stirred at room temperature for 30 minutes. Methylene chloride is added to the reaction mixture, which is washed in succession with 10% strength sodium thiosulphate solution, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentrating by evaporation the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-bromo-3-methyl-6-morpholinobenzofuran-2(3H)-one having a melting point of 99°-100° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>O1CCCC1>[CH:1]1([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A solution of 23.6 g (0.24 mol) of cyclohexylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 30.0 g (0.16 mol, 69% yield) of a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.CCCCC.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](F)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)(=[O:36])=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Reactant: O=S(=O)(F)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)n1c(S(=O)(=O)c2ccc(F)cc2)cc2ccccc21
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 43.1 %

Procedure:
A solution of 1-indole carboxylic acid tert-butyl ester (1.88 g, 8.65 mmol) in 100 mL of anhydrous THF was cooled to −78° C. in a dry ice/acetone bath under an argon gas blanket. A fresh commercial (Aldrich) 1.7 M solution of t-BuLi in pentane (10.2 mL, 17.3 mmol, 2.0 eq) was slowly added to the stirring mixture via syringe. During the addition, the solution turned from a light amber-red color to a dark, orange-burgundy color. After the addition was complete, the reaction mixture was allowed to stir for 45 minutes at −78° C. and then 4-fluorobenzenesulfonyl fluoride was slowly added to the reaction mixture while carefully maintaining an internal temperature of <−65° C. The reaction mixture was kept at −75 to −78° C. for a period of 20 minutes after the addition was complete then was allowed to warm to room temperature, where it remained for 2 h. The reaction mixture was poured into 500 mL of saturated NH4Cl solution, diluted with 500 mL of EtOAc and mixed well. The pale, amber-orange organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a dark amber oil which was silica-gel chromatographed, gradient eluting with 10% EtOAc/Hexane followed by CHCl3 to give 1.40 g, 3.73 mmol, 43.1% yield of the 2-(4-Fluoro-benzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester as an amber oil which solidified on standing to a pale reddish-tan solid which had a melting point range of 88–93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](N(OC)C)=[O:14])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25](=[O:32])(=[O:31])[N:26]=CN(C)C)=[CH:21][CH:20]=3)[C:9]=2[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:4][CH:3]=1.[CH2:37]1COC[CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:14])[CH2:37][CH3:38])=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH2:26])(=[O:32])=[O:31])=[CH:21][CH:20]=3)[C:9]=2[CH2:33][N:34]([CH3:36])[CH3:35])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(CN(C)C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Yield: 19.28 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.48 g, 3.6 ml 1M solution in THF, 3.64 mmol) was added drop wise to a stirred solution of 5-(4-chlorophenyl)-4-((dimethylamino)methyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N-methylthiophene-2-carboxamide (compound 35e, 0.4 g, 0.72 mmol) in anhydrous THF (20 ml) at 25° C. The reaction mixture was then heated at about 70 to about 75° C. for 2 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the reaction mixture was quenched by addition of a saturated solution of ammonium chloride (15 ml). The mixture so formed was then extracted with ethyl acetate (2×30 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic layer was evaporated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 60% ethyl acetate in hexanes as an eluent to obtain the title compound (0.065 g, 19.28%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][NH:7][C:8]1[CH:13]=[C:12](I)[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH2:38])O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[NH2:38])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Reactant: COc1ccc(CNc2cc(I)cc(C(F)(F)F)n2)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(CNc2cc(-c3ccncc3N)cc(C(F)(F)F)n2)cc1OC
Yield: 38 %

Procedure:
Method 26 was followed using N-(3,4-dimethoxybenzyl)-4-iodo-6-(tri-fluoromethyl)pyridin-2-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3 equiv.), Pd(dppf)Cl2 DCM (0.10 equiv.) in DME/2M Na2CO3 (3:1, 0.07 M) at 50° C. for 45 min. Purification via reverse phase HPLC afforded N2-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4,4′-bipyridine-2,3′-diamine in 38% yield. LCMS (m/z): 402.1 (MH+); LC Rt=3.0 min.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:34]2[C:35]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[N:36][N:37]([CH2:47][CH3:48])[C:38]=2[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:34]2[C:35]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[N:36][N:37]([CH2:47][CH3:48])[C:38]=2[NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:43])[CH3:44])[CH2:31][CH:32]=[O:33])=[CH:26][CH:25]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CCO)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: O
Product: CCn1nc(-c2ccccn2)c(C(CC=O)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.4 %

Procedure:
Dess-Martin periodinane (0.203 g, 0.480 mmol) was added in one portion to a solution of tert-butyl (4-(1-(4-bromophenyl)-3-hydroxypropyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.334 g, 0.480 mmol) and DCM (5.00 mL) under N2 at about 0° C. After about 5 min, the ice bath was removed. After about 30 min, Dess-Martin periodinane (0.203 g, 0.480 mmol) was added in one portion. After about 30 min, the reaction mixture was cooled to 0° C. then saturated aqueous NaHCO3 (5 mL), water (5 mL), 10% aqueous sodium thiosulfate (5 mL), and DCM (10 mL) were added. After stirring vigorously for about 15 min, the layers were separated and the aqueous layer was extracted with DCM (10 mL). The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 20-75% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford tert-butyl (4-(1-(4-bromophenyl)-3-oxopropyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.0848 g, 0.170 mmol, 35%) as a pale yellow solid. LC-MS (Table 1, Method g) Rt=2.61 min; m/z 499 and 501 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH:16]1([CH2:19][CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[C:22]2=[O:31])[CH2:18][CH2:17]1>C1COCC1.ClCCl>[CH:16]1([CH2:19][CH2:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]([OH:30])([C:7]3[C:8]([OH:10])=[CH:9][C:4]4[O:3][CH2:2][O:1][C:5]=4[CH:6]=3)[C:22]2=[O:31])[CH2:18][CH2:17]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (1.25 g, 9.06 mmol) in THF (20.0 mL) was added dropwise a solution of isopropylmagnesium chloride solution (4.53 mL, 9.06 mmol, 2.0 M in THF) at 0° C. over 5 min. The reaction mixture was stirred for 0.5 h upon which time colorless precipitate was formed. After the solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (20.0 mL) and cooled to 0° C. A solution of 1-(2-cyclopropylethyl)-1H-indole-2,3-dione (1.77 g, 8.23 mmol) in dichloromethane (20.0 mL) was added to the above solution at 0° C. The resulting mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride solution (30.0 mL). The organic layer was separated and washed with water (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from ethyl acetate and ether to give the title compound (2.22 g, 76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.52 (s, 1H), 7.46 (d, 1H), 7.37 (dt, 1H), 7.18 (dt, 1H), 6.90 (d, 1H), 6.56 (s, 1H), 6.23 (s, 1H), 5.84 (dd, 2H), 4.55 (s, 1H), 3.87-3.63 (m, 2H), 1.64-1.44 (m, 2H), 0.68-0.55 (m, 1H), 0.41-0.27 (m, 2H), −0.02- (−0.07) (m, 2H); 13C NMR (75 MHz, CDCl3) δ 179.1, 152.4, 148.8, 142.7, 141.3, 130.3, 129.1, 126.3, 123.7, 117.3, 109.5, 106.9, 101.9, 101.4, 79.3, 40.6, 32.2, 8.6, 4.3, 4.2; MS (ES+) m/z 337.6 (M−17).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[NH2:3].[F:11][C:12]([F:19])([F:18])[C:13](=O)[CH2:14][C:15]#[N:16].Cl>C(O)C>[CH3:10][C:7]1[N:8]=[CH:9][C:4]([N:2]2[C:15]([NH2:16])=[CH:14][C:13]([C:12]([F:19])([F:18])[F:11])=[N:3]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(NN)cn1
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-n2nc(C(F)(F)F)cc2N)cn1
Yield: 17.3 %

Procedure:
A mixture of 5-hydrazinyl-2-methylpyridine hydrochloride (5.0 g, 31 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.0 g, 65 mmol) in ethanol (50 mL) was treated with cone HCl (5.0 mL, 60 mmol) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the residue was dissolved in EtOAc and neutralized with saturated Na2CO3 solution. The organic layer was dried (Na2SO4), concentrated in vacuo and purified by pre-HPLC to give 2-(6-methyl-pyridin-3-yl)-5-trifluoromethyl-2H-pyrazol-3-ylamine (1.3 g, 10% yield over 2 steps). 1HNMR (400 MHz, CDCl3) δ 9.17 (d, J=1.6 Hz, 1 H), 8.40 (dd, J=8.4, 2.4 Hz, 1 H), 7.62 (d, J=8.4 Hz, 1 H), 5.97 (s, 1 H), 2.80 (s, 3 H); MS (ESI) m/z: 243.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[CH3:22][C:23]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])[CH3:24].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[CH2:34][C@@H:30]([NH:29][C:27](=[O:28])[O:26][C:23]([CH3:24])([CH3:22])[CH3:25])[C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 93.8 %

Procedure:
Preparation of example 154 from the title compound of Example 7 (hydrochloride) (40 mg, 0.128 mmol), (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-naphthalen-2-ylpropanoic acid (58 mg, 0.192 mmol), triethylamine (0.054 mL, 0.384 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (73 mg, 0.192 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (69 mg, 0.120 mmol) as a yellow powder in 94% yield.
Reaction SMILES: C[S-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([S:11]([CH3:14])(=O)=O)[N:8]=[C:7]([NH:15][CH:16]([CH3:18])[CH3:17])[C:6]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]>C1COCC1.CN(C=O)C.CC(OC)(C)C>[Cl:4][C:5]1[N:10]=[C:9]([S:11][CH3:14])[N:8]=[C:7]([NH:15][CH:16]([CH3:18])[CH3:17])[C:6]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F
Agent: C[S-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NC(C)C)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 120.8 %

Procedure:
70 mg (1.0 mmol) of sodium thiomethoxide, dissolved in 3 ml of anhydrous THF, were added to a solution of 216 mg (0.5 mmol) of [6-chloro-2-methanesulfonyl-5-(2,4,6-trifluorophenyl)pyrimidin-4-yl]isopropylamine (abbr. sulfone 2) in 2 ml of anhydrous DMF. The mixture was stirred at 20-25° C. for 16 hours and then diluted with MTBE, washed with water and dried. Distillative removal of the solvent and chromatography on silica gel gave 0.21 g of the title compound of m.p. 112-116° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1.[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[NH:38][N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:22][C:23]([NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]2[N:33]([CH2:42][C:43]#[C:44][CH3:45])[C:34]3[C:39](=[O:40])[N:38]([CH2:2][C:3]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[O:7][C:6]5[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=5[N:4]=4)[N:37]=[CH:36][C:35]=3[N:41]=2)[CH2:27]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: ClCC1=Nc2ccccc2Oc2ccccc21
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cn[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2cnn(CC3=Nc4ccccc4Oc4ccccc43)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
317 mg 11-chloromethyl-dibenzo[b,f][1,4]oxazepin are added to 400 mg 2-[3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 276 mg potassium carbonate in 4 ml N,N-dimethylformamide. The reaction mixture is stirred for two hours at 80° C. For working up it is combined with water and the precipitate formed is suction filtered. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:13][C:12](=[O:14])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[O:14]=[C:12]1[NH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)=[CH:9][CH:10]=[CH:11]1
Reactant: O=C1CCC(c2cccc(=O)[nH]2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cccc(=O)[nH]3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 6-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: Cl.[NH2:2][NH2:3].[C:4]([CH:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:8]([CH3:19])([CH3:18])[C:7]1=O)#[N:5]>CCO>[NH2:5][C:4]1[C:6]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:8]([CH3:19])([CH3:18])[C:7]=2[NH:2][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C(=O)C1(C)C
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c(N)n[nH]c2C1(C)C
Temperature: 85 °C
Reaction time: 18 h
Yield: 45.2 %

Procedure:
Hydrazine hydrochloride (4.95 g, 72.4 mmol) was added to a solution of tert-butyl 4-cyano-2,2-dimethyl-3-oxopyrrolidine-1-carboxylate (11.5 g, 48.2 mmol) in EtOH (300 mL) and the reaction mixture was stirred at 85° C. for 18 hours then concentrated in vacuo. The residue was taken up in EA (200 mL), washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (3% MeOH in EA) afforded the title compound (5.5 g, 46%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.12 (s, 1H), 5.05 (s, 2H), 4.11-4.07 (m, 2H), 1.50-1.48 (m, 6H), 1.44-1.41 (m, 9H).
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4]1.C([O-])(=O)C.[Na+].O>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:3][CH:4]=1
Reactant: BrBr
Reactant: c1ccc2sccc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1csc2ccccc12

Procedure:
A solution of bromine (20.4 ml, 0.40 mole) in chloroform (100 ml) was added dropwise over 1 hour to a stirred mixture of benzothiophene (53.6 g, 0.40 mole) and anhydrous sodium acetate (54.4 g, 0.68 mole) in chloroform (300 ml) at room temperature. The reaction mixture became much thicker during the addition, so a further 300 ml of chloroform was added to aid stirring. After completing the addition, the reaction mixture was stirred for a further 2 hours and then water added (200 ml) to dissolve the inorganic solid. The chloroform layer was separated and washed with water (1×200 ml), sodium hydrogen carbonate solution (1×200 ml) and brine (1×200 ml); then dried (MgSO4) and evaporated to dryness to give a quantitative yield of the title compound as a yellow oil.