Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]([N:10]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]3)=[C:8]([N+:24]([O-])=O)[CH:7]=[N:6]2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([NH:34][C:35]1[S:39][C:38]([C:40]2[C:45]([F:46])=[CH:44][CH:43]=[CH:42][C:41]=2[F:47])=[N:37][C:36]=1[C:48](O)=[O:49])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[F:47][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]([F:46])[C:40]=1[C:38]1[S:39][C:35]([NH:34][C:32](=[O:33])[O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[C:36]([C:48](=[O:49])[NH:24][C:8]2[CH:7]=[N:6][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:9]=2[N:10]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]2)[N:37]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2CC2CC2)CC1)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 77 %

Procedure:
(R)—N-(1-(1-cyclopropylmethyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid were reacted to give (R)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-cyclopropylmethyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (136 mg, 77%). 1H-NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.75 (s, 1H), 7.95 (s, 1H), 7.41-7.36 (m, 1H), 7.10-7.02 (m, 2H), 6.37 (d, J=8 Hz, 1H), 4.25-4.10 (m, 1H), 3.90-3.83 (m, 2H), 3.43-3.31 (m, 2H), 3.30-3.15 (m, 2H), 2.25-2.05 (m, 2H), 2.03-1.70 (m, 4H), 1.57 (s, 9H) 1.35-1.20 (m, 1H), 0.64-0.59 (m, 2H), 0.43-0.38 (m, 2H).
Reaction SMILES: B.[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)(=[O:12])C.B.[CH2:20]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=N[CH:27]=1)[CH3:21]>>[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([OH:12])[CH2:20][C:22]1[CH:23]=[CH:24][CH:25]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Reactant: CCc1ccc(C)nc1
Agent: B
Product: OCCc1ccccc1
Product: OCc1ccccc1

Procedure:
The chemoselectivity of the new borane complexes with substituted pyridines (1) in reduction reactions was investigated in a competitive reactivity study by reacting equimolar amounts of benzaldehyde and acetophenone with 5-ethyl-2-methylpyridine borane (1 equivalent of borane hydride relative to 1 equivalent of benzaldehyde, see example 10). The reaction was immediate and exothermic taking the reaction temperature to 70° C. The benzaldehyde was reduced much faster than the ketone, resulting in a 91:9 ratio of benzyl alcohol to phenethylalcohol. Of the combined carbonyl substrates, 37% was reduced and 63% remained unreduced (50% expected), which indicated that two of the three available hydride atoms were available for the reduction under these conditions. It is common that carbonyl reductions with borane frequently stop when two of the three borane hydride atoms have reacted, owing to the poor reactivity of the dialkoxyborane [(RO)2BH] species formed.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[O:19]([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:32][C:29]3[CH:28]=[CH:27][C:26]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:31][CH:30]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C
Yield: 84.3 %

Procedure:
Compound 396A (1.85 g, 85%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (1.4 g, 5.32 mmol) and 4-phenoxy-phenylamine (1.1 g, 5.94 mmol) by a route analogous to that used for the preparation of compound 388D.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1/[CH:11]=[CH:10]/[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a suspension of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (150 mg, 0.47 mmol) in THF (1.5 mL) and methanol (0.5 mL) was added a solution of lithium hydroxide monohydrate (39.2 mg, 0.94 mmol) in water (1.5 mL) added and the resulting mixture stirred at room temperature for 1 h. The mixture was acidified to pH 4 with HCl (1 N) and cooled to 0° C. The precipitate was filtered off and dried to afford the title compound (134 mg, 93%) which was obtained as a white solid. MS: m/e=305.4 [M−H]+.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[C:13]1(=[O:26])[C:18]2[NH:19][C:20]3[C:25]([C:17]=2[CH2:16][CH2:15][NH:14]1)=[CH:24][CH:23]=[CH:22][CH:21]=3.Br[CH:28]([CH2:34]CCC)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([CH:28]([CH2:7][CH2:5][CH3:6])[CH2:34][N:14]1[CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]=2[C:13]1=[O:26])=[O:30])[CH3:33]
Reactant: CC(C)NC(C)C
Reactant: O=C1NCCc2c1[nH]c1ccccc21
Reactant: CCCCC(Br)C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(CN1CCc2c([nH]c3ccccc23)C1=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 16 h
Yield: 39.1 %

Procedure:
A solution of 0.38 ml (2.8 mmol) of diisopropylamine in 25 ml of dry tetrahydrofuran was cooled under N2 atmosphere to -78° C. and treated with 1.1 ml (2.8 mmol) of n-butyllithium. The resulting solution was warmed to 0° C. for 5 min, recooled to -78° C. and treated with a solution of 250 mg (1.34 mmol) of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (J. Chem. Soc. 1960, 4699) in 5 ml of tetrahydrofuran. The solution was allowed to warm to 0° C. followed by treatment with 0.25 ml (1.4 mmol) of ethyl 2-bromohexanoate. The resulting solution was stirred at ambient temperature for 16 h, partitioned between ether and aqueous ammonium chloride, washed with saturated brine, dried over MgSO4, and concentrated. Purification of the residue by silica gel chromatography using 3:1 hexane:ethyl acetate gave 172 mg (39%) of the desired compound as a colorless oil. 1H NMR (CDCl3) δ 0.91 (br t,3H), 1.27 (5,J=7 Hz,3H), 1.4 (m,4H), 1.86 (m,1H), 2.10 (m,1H), 3.10 (m,2H), 3.66 (ddd,J=13,8,6 Hz,1H), 3.81 (ddd,13,8,6 Hz,1H), 4.2 (m,2H), 5.39 (dd,J=10,5 Hz,1H), 7.15 (td,J=7,1 Hz,1H), 7.31 (td,J=7,1 Hz,1H), 7.47 (d,J=7 Hz,1H), 7.60 (d,J=7 Hz,1H), 9.81 (br s,1H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)[CH3:2].F[B-](F)(F)F.[O:20]=[C:21]1C=CC=C[N:22]1OC(N(C)C)=[N+](C)C.O.OC1C2N=N[NH:42]C=2C=CC=1.C(N(C(C)C)C(C)C)C>ClCCl.O>[CH:21]([NH:22][NH:42][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])=[O:20]
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Reactant: Oc1cccc2[nH]nnc12
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)NNC=O)c(C)nc1OC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 59.4 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) is dissolved in dichloromethane (30 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (990 mg, 3.33 mmol) is added, followed by hydroxybenzotriazole hydrate (510 mg, 3.33 mmol). The resulting mixture is stirred at rt for 40 min to give a suspension, which is treated with formyl hydrazide (231 mg, 3.85 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol) to give a solution. After stirring at rt for 23 hr, LC/MS shows the reaction to be incomplete. The reaction is allowed to stir for a further 97 hr at room temperature. The reaction is diluted with water and the mixture is extracted with six portions of dichloromethane, the combined extract is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (1:1, increasing to 1:2). Fractions containing the product are combined, and the product triturated with ether to give 5-ethyl-6-methoxy-2-methyl-nicotinic acid N′-formylhydrazide (361 mg) as a white solid that was used without further purification. MS: m/e=238 (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 9.05 (1H, br.s), 8.71 (1H, br.s), 8.20 (1H, s), 7.49 (1H, s), 3.97 (3H, s), 2.58 (3H, s), 2.56 (2H, q), 1.16 (3H, t).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:5]=[C:4]([OH:15])[CH:3]=1.O[C:17]([C:20]1[CH2:25][CH:24]=[C:23]([O:26][CH3:27])[CH2:22][CH:21]=1)([CH3:19])[CH3:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH3:27][O:26][C:23]12[CH2:22][CH:21]([C:20](=[C:17]([CH3:18])[CH3:19])[CH2:25][CH2:24]1)[C:3]1=[C:4]([OH:15])[CH:5]=[C:6]([CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH3:9])[CH:7]=[C:2]1[O:1]2
Reactant: COCCCC(C)c1cc(O)cc(O)c1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: COCCCC(C)c1cc(O)c2c(c1)OC1(OC)CCC(=C(C)C)C2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.05 g. of 1,3-dihydroxy-5-(5-methoxy-2-pentyl)- benzene and 1.06 g. (6 mmoles) of 1-(2-hydroxy-2-propyl)- 4methoxy-1,4-cyclohexadiene [R.A. Archer et. al. J. Org. Chem., 42, 2277 (1977)]are dissolved in 25 ml. of abs. benzene. 0.5 ml. (3.4 mmoles) of borontrifluoride etherate are added and the mixture is stirred at room temperature for 5 hours. Further 0.40 g. (2.4 mmoles) diene are added and the mixture is stirred overnight. The solution is poured off from the precipitated gum and extracted with 3 ×10 ml. of 1 N sodium hydroxide. The benzene solution is dried, evaporated and the residue is chromatographed on a column with a 8.1 mixture of benzene: ethyl acetate. The product is a colorless resin.
Reaction SMILES: C([Mg]Cl)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15](OCC)=[O:16])=[CH:9][CH:8]=1.Cl.[CH3:22][NH:23][O:24][CH3:25]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10](/[CH:13]=[C:14](\[CH3:20])/[C:15]([N:23]([O:24][CH3:25])[CH3:22])=[O:16])=[CH:11][CH:12]=1
Reactant: CNOC
Reactant: CCOC(=O)/C(C)=C/c1ccc(F)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)/C(C)=C/c1ccc(F)cc1
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of isopropylmagnesium chloride (2.0 M in THF, 59.1 mL, 118 mmol) was added dropwise via addition funnel to a mixture of Example 1A (5.47 g, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.12 g, 52.5 mmol) in THF (100 mL) at 0° C. Upon complete addition, the reaction was allowed to proceed 2 hr at 0° C. The reaction was quenched by slow addition of saturated aq NH4Cl solution (70 mL). The mixture was stirred 60 min, then partitioned between EtOAc (50 mL) and H2O (100 mL). The separated aqueous phase was extracted with EtOAc, and the combined organic layer was washed with 1 N aq HCl and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (Analogix® Intelliflash 280; SF65-400 g column; 20% to 60% EtOAc/hexanes; 0-40 min) to give the title compound (5.06 g, 22.7 mmol, 86% yield) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.50-7.40 (m, 2H), 7.29-7.18 (m, 2H), 6.72 (s, 1H), 3.65 (s, 3H), 3.19 (s, 3H), 2.01 (d, J=1.5 Hz, 3H). MS (DCI+) 224 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>C(Cl)Cl>[F:11][CH:10]([F:12])[C:7]1[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:5][C:4]([CH2:3][NH:2][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[CH:9][N:8]=1
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(CNC(=O)C(C)C)cnc1C(F)F
Yield: 73.6 %

Procedure:
In a thermally controlled reactor stir a mixture of ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (198 g, 742.4 mmol, 1.0 equiv), DCM (3040 mL), and DIPEA (520 mL, 2.98 mol, 4 equiv), then add a solution of isobutyryl chloride (95 mL, 903 mmol, 1.2 equiv) at such a rate so that the internal temperature is held between 18° C. and 22° C. Stir for 90 min. Extract the reaction mixture with NaHCO3 (sat., 1 L). Add water (1 L) and DCM (1 L), and filter the resulting suspension through diatomaceous earth. Combine all organic phases, and dry over MgSO4. Remove the solids by filtration, and concentrate the filtrate under reduced pressure. Purify the resulting material by slurrying with iso-hexane:Et2O [1:1, 1 L]. Collect the solids by filtration, wash with cold iso-hexanes (500 ml), and dry under vacuum at 50° C. to give the title compound as an off-white crystalline powder (164 g). MS (m/z) 301 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][C:22](=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(=O)(O)[O-].[Na+].[C:44](OCC)(=[O:46])[CH3:45]>N1C=CC=CC=1>[C:32]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]([NH:21][C:22](=[O:31])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:30][C:44](=[O:46])[CH3:45])=[CH:28][CH:29]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1)(=[O:34])[CH3:33]
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cc1ccc(O)cc1)Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(OC(C)=O)cc3)nc2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 60.7 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-hydroxyphenyl)-2-[(4-hydroxyphenyl)acetylamino]pyrazine (coelenteramide) (c-4) (prepared by the method described in Inouye, S. & Hosoya, T., Biochem. Biophys. Res. Commun., 386, 617-622 (2009)) (410 mg, 997 μmol) was dissolved in pyridine (11 mL) and cooled to 0° C. To this was added acetic anhydride (475 μL, 5.02 mmol) and stirred for 22 h after warming to room temperature. To this were added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction, and after separating the aqueous layer and organic layer, the organic layer was washed twice with water and once with saturated brine. The precipitate in the organic layer was collected by filtration and dried in vacuo to give 5-(4-acetoxyphenyl)-2-(4-acetoxyphenyl)acetylamino-3-benzylpyrazine (c-29) as a colorless solid (300 mg, 60.7%). Rf=0.28 (n-hexane/ethyl acetate=1/1). Mp. 225-227° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 318 (4.14), 290 (4.12), 259 (4.19). 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.29 (s, 3H), 3.71 (s, 2H), 4.11 (s, 2H), 7.08 (t, J=8.6 Hz, 4H), 7.15 (t, J=7.8 Hz, 1H), 7.21 (t, J=7.8 Hz, 2H), 7.24-7.29 (AA′BB′, 2H), 7.34-7.40 (AA′BB′, 2H), 8.08-8.14 (AA′BB′, 2H), 8.95 (s, 1H), 10.67 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.89, 20.92, 41.6, 121.8 (2C), 122.5 (2C), 126.3, 127.8 (2C), 128.3 (2C), 128.9 (2C), 130.3 (2C), 132.9, 133.2, 137.9, 138.1, 144.4, 147.5, 149.3, 150.6, 151.7, 169.1, 169.3, 169.9 (one carbon at benzyl position was unobservable due to overlapping with the septet peak of DMSO). IR (KBr, cm−1) 515, 590, 654, 704, 854, 918, 1016, 1157, 1190, 1211, 1238, 1346, 1371, 1418, 1449, 1493, 1543, 1672, 1751, 3287. HRMS (FAB+) m/z 496.1863 (M+H, C29H26N3O5 requires 496.1872).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([I:16])[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.CCOC(C)=O>[I:16][C:14]1[CH:13]=[N:12][N:11]([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=1
Reactant: Ic1cnn(C2CCC3(CC2)OCCO3)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A solution of 1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-4-iodo-1H-pyrazole (2.81 g; 8.41 mmol; 1.00 eq.) and pyridinium para-toluenesulfonate (4.23 g; 16.8 mmol; 2.0 eq.) in acetone (40 mL) and water (40 mL) was heated at reflux O/N. It was then allowed to cool to RT and diluted with EtOAc. Aqueous phase was extracted with EtOAc (twice) and combined organic phases were washed with water and brine, dried over sodium sulftate, filtered and concentrated to give the title compound as a white powder (2.34 g, 96%). HPLC (Condition A): Rt 2.83 min (purity 99.2%). MS (ESI+): 291.1.
Reaction SMILES: [CH2:1]([CH:8]1[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH:11](C(OCC)=O)[CH2:10][N:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1=O.[ClH:30]>>[ClH:30].[CH2:1]([CH:8]1[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[CH2:11][CH2:10][N:9]1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CN(C)C(Cc2ccccc2)C(C)(C)C1=O
Agent: Cl
Agent: O=C1CCCCN1
Product: CN1CCC(=O)C(C)(C)C1Cc1ccccc1
Yield: 75 %

Procedure:
A solution of 217 g of the hydrochloride of ethyl 2-benzyl-4-oxo-1,3,3-trimethyl-5-piperidine carboxylate in 6 N hydrochloric acid is refluxed for 40 minutes. The piperidone is gathered as the hydrochloride in the same way as described in example 12. Yield 75%; melting point 177° - 179° C, with decomposition.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5].[NH3:22]>C(O)C.C1COCC1>[NH2:22][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([CH3:21])[CH:14]=2)(=[O:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: COc1cc(C)cc(S(=O)(=O)c2cccc(F)c2C#N)c1
Reactant: N
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(C)cc(S(=O)(=O)c2cccc(N)c2C#N)c1
Temperature: 130 °C
Yield: 34 %

Procedure:
A solution of 0.3 g (0.00098 mol) of 2-fluoro-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile (Example 25) in 10 mL of absolute ethanol and ca. 2 mL of THF was saturated with ammonia. The resultant solution was sealed in a glass-lined Parr bomb and heated to 130° C. for 4 h. The solvent was removed in vacuo. 20 mL of 1 NaOH was added. This aqueous solution was extracted with 3×50 mL of EtOAc. The EtOAc solution was dried over MgSO4. After solvent removal, the crude product was recrystallized from absolute ethanol to give 0.1 g (34%) of 2-amino-6-[(3-methyl-5-methoxyphenyl)sulfonyl]benzonitrile: mp 166°-168° C.; NMR (Me2SO-d6, 200 MHz δ 2.4 (s, 3H), 3.87 (s, 3H), 6.7 (br s, 2H), 7.13 (apparent d, 1H), 7.2 (unresolved s, 1H), 7.3-7.5 (m, 2H), 7.57 (apparent t, 1H). Anal. Calc. for C15H14N2O3S: C, 59.59; H, 4.67;N, 9.27; S, 10.6. Found: C, 59.67;H, 4.71;N, 9.25; S, 10.51.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([CH3:11])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:17](=[O:19])=[O:18]>O1CCCC1.C(OCC)C>[CH3:11][C:9]1[S:8][C:7]2[C:2]([C:17]([OH:19])=[O:18])=[CH:3][CH:4]=[CH:5][C:6]=2[CH:10]=1
Reactant: O=C=O
Reactant: Cc1cc2cccc(Br)c2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2cccc(C(=O)O)c2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
The solution of 7-bromo-2-methylbenzo[b]thiophene (508) (0.908 g, 4.0 mmol) in tetrahydrofuran (16 mL) was cooled to −78° C. under nitrogen. n-butyllithium (2.40 mL, 6.0 mmol, 1.0M in Hexanes) was added dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 h, then poured on to the mixture of dry ice in ethyl ether (30 mL). The reaction was stirred to reach room temperature for 5 hours, followed by washing with 1N HCl, brine and dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained white solid was washed with hexanes to provide 2-methylbenzo[b]thiophene-7-carboxylic acid (509) (0.240 g, 31.2%). LC-MS ESI m/z: found 191.0 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:13]Br.S([O-])(O)=O.[Na+]>[Fe](Cl)(Cl)Cl.O>[Br:13][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[CH:10]([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: CC(C)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc([N+](=O)[O-])cc1Br
Yield: 101.1 %

Procedure:
A solution of p-nitrocumene (X) (50 g, 0.300 mol, GC purity: 99.1%) and iron(III) chloride was heated to 40° C. and bromine (59.92 g, 0.375 mol) was added dropwise over a period of 3 hours. The reaction mixture was poured into 120 ml of water, sodium hydrogensulphite (40% strength in water, 20.81 g, 0.078 mol) was added dropwise and the mixture was extracted with 100 ml of chlorobenzene. After phase separation, the chlorobenzene phase was washed with 100 ml of 5% strength aqueous HCl. Removal of the chlorobenzene under reduced pressure gave 2-bromo-1-isopropyl-4-nitrobenzene (74.05 g, 96.9 GC-% by area, 98% of theory) as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Reactant: OB(O)c1ccccc1
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(C)nsc2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester and phenyl boronic acid: MS (m/z) 343.1 (M+1).
Reaction SMILES: CN(C)C.[C:5]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl.C(OCC)(=O)C>[C:5]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[N:16]([C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:15]2=[O:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.43 g of trimethylamine were added to a solution of 9.0 g of 5-(4-acetoxybenzyl)thiazolidine-2,4-dione [prepared as described in step (b) above] in 70 ml of methylene chloride, and a solution of 9.45 g of triphenylmethyl chloride in 30 ml of methylene chloride was added dropwise to the resulting mixture. The mixture was then stirred at room temperature for 1 hour, after which it was allowed to stand overnight at the same temperature. At the end of this time, the reaction mixture was mixed with water and ethyl acetate, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The crystals which separated out on distilling off the solvent under reduced pressure, were washed with a mixture of hexane and ethyl acetate and dried, to give the title compound.