Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=O)[CH:5]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:23]=[CH:22][CH:21]=[C:6]([C:7]2[S:26][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)[CH:5]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2ncc(-c3ccc(OC)cc3)s2)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a suspension of 1.4 g (4.3 mmol) N-[2-(4-Methoxy-phenyl)-2-oxo-ethyl]-isophthalamic acid methylester from Preparation 2 in 30 mL of dry dioxane was added 1.1 g (5.2 mmol) of P2S5 in one portion. The resulting mixture was warmed to 50° C. for 1 hour before cooling to room temperature and adding about 60 ml water. Stirred 2 hours and then filtered off solid product. Triturated in hot MeOH and filtered. Dissolved in THF and filtered through a plug of flash silica gel with THF eluent. Concentration gave 1.4 g (100%) of desired product. Used directly in the procedure of Preparation 11 without characterization.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[C:11](=[O:14])([O-])[O-].[K+].[K+]>N1CCCC1=O.O.[Cu]>[N+:8]([C:4]1[CH:3]=[C:2]([N:8]2[CH2:4][CH2:3][CH2:2][C:11]2=[O:14])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Cu]
Agent: O=C1CCCN1
Agent: [K+]
Solvent: O
Product: O=C1CCCN1c1cccc([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 29.1 %

Procedure:
A suspension of 1-iodo-3-nitrobenzene (24.9 g, 0.1 mol), copper bronze (320 mg, 5 mmol) and potassium carbonate (15.2 g, 0.11 mol) in 2-pyrrolidinone was heated under a stream of nitrogen at 200° C. for 45 minutes. The reaction was cooled to ambient temperature, diluted with water (2000 ml) and extracted with diethyl ether (800 ml). The organic phase was then washed with water (2×800 ml), brine and dried over anhydrous sodium sulphate containing decolourising charcoal (2 g). Filtration and evaporation to dryness gave a yellow solid which was triturated with isohexane to give 1-(3nitrophenyl)pyrrolidin-2-one as a yellow powder (3.0 g, 15%). δH (360 MHz, CDCl3) 2.19-2.27 (2H, m), 2.67 (2H, t, J 8), 3.94 (2H, t, J 7), 7.54 (1H, t, J 8), 8.00 (1H, ddd, J 8, 2 and 1), 8.22 (1H, ddd, J 8, 2 and 1), 8.35 (1H, t, J 2).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=O.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:21]=[N:24][OH:25]
Reactant: NO
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.25 g) in ethanol (3 ml) was added hydroxylamine hydrochloride (0.075 g), sodium acetate (0.1 g) and water (0.1 ml). After stirring at room temperature overnight the mixture was evaporated. The residue was taken up in ether and washed with water, then brine, then dried and evaporated. The residue was crystallised from propan-2-ol/water and further purified by column chromatography on silica gel eluted with dichloromethane then dichloromethane:methanol (99:1). After combination and evaporation of suitable fractions the residue was further purified by column chromatography on silica gel eluted with ether. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 175-178° C.
Reaction SMILES: C(O)C1C=CC=CC=1.[Si:9]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:38])[CH2:29][CH2:30]2)[CH:25]=[C:24]3[CH3:39])[CH2:21][CH2:20]1)[CH3:18])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>[Pd].CCCCCCC>[Si:9]([O:16][CH:17]([C@@H:19]1[C@:36]2([CH3:37])[C@H:22]([C@H:23]3[C@H:33]([CH2:34][CH2:35]2)[C@:31]2([CH3:32])[C:26](=[CH:27][C:28](=[O:38])[CH2:29][CH2:30]2)[CH2:25][C@@H:24]3[CH3:39])[CH2:21][CH2:20]1)[CH3:18])([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:11])[CH3:10]
Reactant: CC1=CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Agent: [Pd]
Solvent: OCc1ccccc1
Solvent: CCCCCCC
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 80 °C

Procedure:
A slurry of 5% palladium on carbon (7.12 gm) and benzyl alcohol (213 mL) in heptane (356 mL) was refluxed for 20 min. The mixture was cooled to 80° C. and a solution of 20-tert-butyldimethylsilyloxy-7-methyl-pregn-4,6-dien-3-one (71.2 gm, 0.16 mol, product of Step 5) in heptane (427 mL) was added. The slurry was refluxed for 9.5 h. The reaction was cooled to room temperature and filtered through SOLKA FLOK filter aid which was subsequently washed with hexane. The filtrate was extracted with acetonitrile which was subsequently back-extracted with hexane. The heptane and hexane extracts were combined, washed with saturated sodium sulfate and saturated salt solutions, and dried over anhydrous magnesium sulfate. The solution was filtered through a pad of anhydrous sodium sulfate and the solvent removed by rotoevaporation. The title compound was purified by column chromatography on silica gel eluted with 7% ethyl acetate in hexanes.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.C([Li])CCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:32])=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=3)([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:33][CH3:34])[C:14]=1[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:40][CH:41]=1
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (275 mg, 3.31 mmol, prepared according to PCT Int. Appl., 2008098104) was added THF (35 mL) and the colorless solution was cooled to −50° C. Then, n-butyllithium (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise which afforded a dark reddish-brown viscous solution. The mixture was stirred between −20 to −10° C. for 30 minutes, then a homogeneous THF solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (700 mg, 1.44 mmol in 4 mL THF, Intermediate 47: step f) was introduced at 0° C. The reaction mixture became a dark brown color and was allowed to warm gradually to room temperature. The mixture was stirred for 60 minutes at room temperature then quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc, 3×50 mL. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to provide a brown oil. Chromatography on silica gel (1% MeOH-DCM increasing to 5% MeOH-DCM) provided the product as a light brown solid. MS m/e 586.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (d, J=1.8 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.1 Hz, 2H), 7.37 (d, J=7.9 Hz, 3H), 6.93 (q, J=8.1 Hz, 2H), 6.80 (s, 1H), 5.51 (s, 1H), 4.36-4.22 (m, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H). Racemic (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol was separated into its individual enantiomers using the following conditions: Chiralcel OD, 20 uM (Diacel) using ethanol with 242 nM detection to give the first eluting enantiomer Example 77B: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H); and the second eluting enantiomer Example 77C: 1H NMR (500 MHz, CD2Cl2) δ ppm 8.09 (d, J=2.2 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.44-7.36 (m, 3H), 6.95 (q, J=8.1 Hz, 2H), 6.85 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 3.90 (s, 3H), 2.49 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([CH3:23])([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:15][CH2:14]1.[Cl-].[NH4+].C1C[O:29]CC1>CCOC(C)=O>[OH:29][CH:17]([C:16]([CH:13]1[CH2:15][CH2:14]1)([CH3:23])[CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: C1CCOC1
Reactant: COC(=O)CC(C)(C)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(O)C(C)(C)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of diisopropylamine (4.9 mL, 35 mmol) in dry THF (100 mL) at 0° C. under inert atmosphere was added n-butyllithium (14 mL, 35 mmol) dropwise over a period of 5 min. The solution was cooled to −78 ° C. and methyl 3-cyclopropyl-3-methylbutanoate (5.0 g, 32) was added dropwise over a period of 5 min. The solution was stirred at −78 ° C. for 1 h at which time (+)-camphorsulfonyloxaziridine (9.0 g, 39 mmol) was added all at once. The resulting suspension was stirred at −78 ° C. for 30 min and then allowed to warm to ambient temperature over 30 min. EtOAc (100 mL) and saturated aqueous ammonium chloride (50 mL) were added and the organic layer was separated and washed with water (50 mL), dried (MgSO4), and filtered. The solvents were removed under reduced pressure and the resulting oily solid was stirred in ether (50 mL) for 30 min. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure. The residue was purified by flash column chromatography using a gradient elution of 10% to 14% EtOAc in hexanes to give methyl 2-hydroxy-3-cyclopropyl-3-methylbutanoate as a colorless liquid. TLC Rf=0.4 (12% EtOAc-hexanes); HPLC RT=2.72 min (Method A); 1H NMR 400 MHz, CDCl3, 3.92 ppm ((d, J=7.9 Hz, 1H), 3.79 ppm (s, 3H), 2.79 ppm (d, J=7.9 Hz, 1H), 0.84 ppm (s, 3H), 0.83 ppm (m, 1H), 0.80 ppm (s, 3H), 0.32 ppm (m, 2H), 0.20 ppm (m, 2H)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24](I)=[N:25][C:26]=3[C:17]=2[N:16]([CH3:28])[N:15]=1)=[O:13])[CH3:2].[CH3:29][C:30]#[N:31]>>[NH2:31][C@H:30]1[CH2:1][CH2:3][C@H:4]([NH:11][C:24]2[N:23]=[CH:22][C:21]3[CH2:20][CH2:19][C:18]4[C:14]([C:12]([NH:11][C:4]5[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=5[CH2:9][CH3:10])=[O:13])=[N:15][N:16]([CH3:28])[C:17]=4[C:26]=3[N:25]=2)[CH2:5][CH2:29]1
Reactant: CC#N
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(I)nc1-2
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N[C@H]3CC[C@H](N)CC3)nc1-2
Temperature: 110 °C

Procedure:
N-(2,6-diethylphenyl)-8-iodo-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (500 mg, 1.01 mmol) was dissolved in CH3CN (3 ml) and treated with trans-1,4-diaminecyclohexane (346 mg, 303 mmol). The mixture was heated at 110° C. for 10 minutes under microwave irradiation. The solvent was removed under reduced pressure and the crude was purified by column chromatography to afford the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:7][CH2:8][CH:9]=O.C([O-])(O)=O.[Na+]>CO.CC(O)=O.Cl>[Cl:7][CH2:8][CH2:9][N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: O=CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O[C@@H]1CCN(CCCl)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a solution of (R)-3-hydroxypyrrolidine (0.47 g, 5.5 mmol) in MeOH (14.4 mL) and AcOH (1.44 mL) was added chloroacetaldehyde (0.86 mL, 5.5 mmol, 50% in H2O solution) and picolineborane complex (0.58 g, 5.5 mmol). The reaction mixture was stirred at ambient temperature for 0.5 h. Then additional picoline borane complex (0.29 g, 2.7 mmol) was added. The reaction mixture was stirred for an additional 0.5 h. Then the reaction mixture was diluted with HCl (30 mL, 10% in H2O) and stirred for 0.5 h at ambient temperature. The mixture was slowly basified with solid NaHCO3 (7.85 g) and extracted with EtOAc (3×20 mL). The organics extracts were dried (Na2SO4) and concentrated to yield the title compound (0.19 g, 23%) as a light yellow oil. 1H NMR (300 MHz, CD3OD) δ 4.36-4.32 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 2.91-2.76 (m, 4H), 2.66-2.52 (m, 3H), 2.16-2.09 (m, 1H), 1.74-1.70 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]([CH3:15])=[CH2:14])[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([C:9](=[O:11])[CH3:10])[CH2:12][C:13]2([CH3:15])[CH3:14]
Reactant: C=C(C)CN(C(C)=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)N1CC(C)(C)c2cc(F)ccc21
Temperature: 150 °C

Procedure:
According to the procedure described in S. Coulton et al. WO9925709 with the following modifications. N-(4-Fluoro-phenyl)-N-(2-methyl-allyl)-acetamide (5 grams, 24.12 mmol) was added to a microwave tube with aluminum trichloride (7 grams, 52.4 mmol). The tube was capped and heated to 150° C. for 20 minutes under microwave. The slurry was worked up with water and ethyl acetate, the organic layer was extracted with 3 washes of saturated sodium bicarbonate solution and the organic layer was dried over magnesium sulfate. The solution was then filtered and rotary evaporated to yield pure 1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone in quantitative yield. This was converted to the free indoline by suspending the entire 5 grams of product in 20 mL of 6 M HCl and heating in a microwave to 200° C. for 10 minutes. The resulting 5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indole crystallized on cooling as the hydrochloride salt in quantitative yield. This material was identical to the previously reported compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[F:27]>ClCCl.N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)c(F)c1
Yield: 35.8 %

Procedure:
The title compound was synthesized substantially in the same manner as Example 3 by coupling of 2-methyl-6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-ylamine (0.025 g, 0.096 mmol) with 3,4-difluorobenzenesulfonyl chloride (0.061 g, 0.288 mmol) in dichloromethane (3 mL) and pyridine (0.5 mL) to obtain 0.015 g (36%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH3:27])[C:16]1=[O:28])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:17]([CH3:27])[C:16]1=[O:28]
Reactant: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (137 mg, 0.296 mmol) was dissolved in methylene chloride (2 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 2.22 mL, 8.88 mmol) and the slurry was stirred at ambient temperature for 15 minutes. Methanol (1 mL) was added followed by silica gel and the mixture was concentrated to dryness. Crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanamide as a solid. 65.8 mg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH2:19])[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:20]1([CH2:26][C:27](O)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH:14]([CH2:18][NH:19][C:27](=[O:28])[CH2:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccccc1
Reactant: NCC1CN(CCCc2ccc(Cl)c(Cl)c2)CCO1
Solvent: CN1CCCC1=O
Product: O=C(Cc1ccccc1)NCC1CN(CCCc2ccc(Cl)c(Cl)c2)CCO1
Yield: 9.6 %

Procedure:
A mixture of Intermediate 7 (0.030 g) and phenylacetic acid (0.015 g) was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a 600 W microwave oven, at full power, for 4 min. The crude mixture was purified by chromatography on silica gel (Varian Bond-Elut, 1 g) eluting with cyclohexane/ethyl acetate (4:1 followed by 2:1) to give thetitle compound as a colourless gum (0.004 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.Cl.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]2[CH2:58][C:57]3[CH:56]=[N:55][N:54]([CH3:59])[C:53]=3[NH:52][C:51]3[CH:60]=[CH:61][CH:62]=[CH:63][C:50]2=3)=[O:48])=[C:43]([F:64])[CH:42]=1>CN(C=O)C.CCN(C(C)C)C(C)C>[F:64][C:43]1[CH:42]=[C:41]([CH:46]=[CH:45][C:44]=1[C:47]([N:49]1[CH2:58][C:57]2[CH:56]=[N:55][N:54]([CH3:59])[C:53]=2[NH:52][C:51]2[CH:60]=[CH:61][CH:62]=[CH:63][C:50]1=2)=[O:48])[CH2:40][NH:39][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH:25]2[CH2:26][CH2:27]2)[CH2:34][CH2:33]1)=[O:37]
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CN)cc1F)C2
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCN(CC4CC4)CC3)cc1F)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
HBTU (227 mg, 0.6 mmol) was added to a solution of 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (99 mg, 0.45 mmol) in DMF (5 ml) and DIEA (to pH9). The mixture was stirred at room temperature for 1 h. (4-Aminomethyl-2-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E90.2 (116 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloromethane) to give a white solid identified as the title compound (71.5 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38][OH:39]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:39][CH2:38][CH2:37][O:36][CH3:35])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: CSc1nc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)cc(C(F)(F)F)n1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1ccc(S(=O)(=O)[C@H]2CCN(c3cc(C(F)(F)F)nc(SC)n3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[(S)-3-(2-Chloro-4-fluoro-benzenesulfonyl)-pyrrolidin-1-yl]-2-methylsulfanyl-6-trifluoromethyl-pyrimidine (Intermediate of example 42; 300 mg) was dissolved in DMF (5.0 mL). Cs2CO3 (429 mg) and 2-methoxy-ethanol (0.10 mL) were added. The reaction mixture was stirred for 24 h at 25° C. After that, the reaction mixture was diluted with ethyl acetate (20 mL) and extracted with water (10 mL). The organic layers were dried over Na2SO4, filtrated and evaporated to dryness. The crude material was purified by flash chromatography (50 g silica gel; ethyl acetate/n-heptane) to yield a colorless waxy solid (170 mg; 50%) MS: m/z=512.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]#[N:20])[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1.C[Sn]([N:36]=[N+:37]=[N-:38])(C)C.C1(C)C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:14])([CH3:15])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]3[NH:38][N:37]=[N:36][N:20]=3)[S:8][C@H:7]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:6]=2[CH:31]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CC#N)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)CN1C(=O)[C@@H](Cc2nnn[nH]2)S[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Yield: 71.2 %

Procedure:
A heterogeneous mixture of trans-7-chloro-5-(naphthalen-1-yl)-1-neopentyl-1,2,3,5-tetrahydro-2-oxo-4,1-benzothiazepine-3-acetonitrile (75 mg, 167 μmol), trimethyltin azide (70 mg, 334 μmol) and toluene (2 mL) was heated at reflux for 18 hours. Reaction mixture concentrated under reduced pressure and purified by flash column chromatography (80:15:1 chloroform/methanol/ammonium hydroxide) to yield a clear oil which was taken up in ethyl acetate, washed with 0.5 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 58.5 mg (71 %) of the title compound as a white powder.
Reaction SMILES: S1(CCCC1)(=O)=O.[F-:8].[Cs+].Br[C:11]1[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=[C:13]([C:28]#[N:29])[C:12]=1[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31]>CCOCC>[C:28]([C:13]1[C:12]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=[C:11]([F:8])[N:15]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]=2[Cl:27])[N:14]=1)#[N:29]
Reactant: [F-]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1S(=O)(=O)C(F)(F)F
Agent: [Cs+]
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(F)c1S(=O)(=O)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
A mixture of dry sulpholane (15 ml) and 4Å molecular sieve (3.0 g) was stirred under nitrogen with caesium fluoride (2.4 g) at 60° C. for 1,2 hour. To this was added 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethanesulphonylpyrazole (2.0 g) and the mixture stirred at 60° C. for 2 hours, and left overnight at room temperature. This was diluted with ether (50 ml), filtered, and washed with water (100ml). The aqueous layer was reextracted with ether (3×50 ml) and the combined organic solution re-washed with water (4×50ml), dried over anhydrous magnesium sulphate, and evaporated in vacuo to give an oil. Purification by chromatography, eluting with ether/hexane (1:4) gave 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-fluoro-4-trifluoromethanesulphonylpyrazole (0.17 g), m.p. 95°-98° C., in the form of a white solid, after recrystallisation from hexane.