Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](=[O:42])(=[O:41])[N:26]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11]CC)=O.[NH3:43]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](=[O:42])(=[O:41])[N:26]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=4)[C:27]4[S:28][CH:29]=[CH:30][N:31]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([NH2:43])=[O:11]
Reactant: CCOC(=O)COc1cc(F)ccc1-c1nccc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc12
Reactant: N
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4OCC(N)=O)nccc3c2)cc1
Temperature: 60 °C

Procedure:
Ethyl 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetate was dissolved in methanolic ammonia and heated at 60° C. for 16 h in a sealed tube. The reaction mixture was concentrated to obtain 2-(5-fluoro-2-(6-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetamide as light yellow solid. m/z (ESI) 579.2 (M+H)+. This was then dissolved in DCM (1 mL) and 4 drops of TFA were added and the reaction was stirred for 15 min. The reaction mixture was loaded on 10 g silica gel column and eluted with DCM:MeOH (90:10) up to 100% to obtain 2-(5-fluoro-2-(6-(N-(thiazol-2-yl)sulfamoyl)isoquinolin-1-yl)phenoxy)acetamide (3.9 mg, 8.51 μmol, 2.96% yield) as light yellow solid. m/z (ESI) 459.0 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:9]([OH:8])[CH:10]=[N:11]1
Reactant: [H][H]
Reactant: OCCn1cc(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Product: OCCn1cc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 169.3 %

Procedure:
2-(4-(benzyloxy)-1H-pyrazol-1-yl)ethanol (1.81 g, 8.3 mmol) was dissolved in THF (15 mL) under nitrogen. Pd/C (0.22 g, 0.21 mmol) was added and the solution was placed under vacuum and charged with a hydrogen balloon. The mixture stirred at ambient temperature overnight under this hydrogen atmosphere. The solution was filtered through GF/F paper and concentrated to give 1-(2-hydroxyethyl)-1H-pyrazol-4-ol (1.8 g, quantitative).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:30]([NH:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:31])[C:3]1=[O:20]
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N[C@H]2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 216°-219° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=O)[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[F:1][C:2]1[C:7]2[NH:8][C:9](=[S:23])[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cccc(F)c2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1cccc2c1NC(=S)CCN2
Temperature: 80 °C
Yield: 180.5 %

Procedure:
A disposable tube was charged with 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (0.037 g, 0.205 mmol) and THF. Lawesson's Reagent (45.7 mg, 0.113 mmol) was added, and the solution was stirred at 80° C. 1 h. The mixture was concentrated, partitioned between water and ethyl acetate, separated, dried with sodium sulfate, concentrated with celite, and purified by silica gel chromatography (eluting with hexanes/ethyl acetate) to yield 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as an off-white amorphous solid (0.040 g, 0.204 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:12]=[CH:11][NH:8][C:7]=12
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1CCOC1
Product: Clc1nccc2cc[nH]c12
Temperature: -20 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.5 mmol)) in THF (200 mL) at −78° C., was added vinylmagnesium bromide (100 mL, 1.0M in THF) The reaction mixture was stirred at −20° C. for 8 hours, quenched with NH4Cl solution (20%, 150 mL), extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23 g, 26% yield) as a white solid [Z. Zhang, et al., J. Org. Chem., 2002, 67, 2345-23471]. MS (m/z): 153.1 (M+H) (found).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([O:18]C)=O)=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.O.[NH2:21][NH2:22]>C(O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([NH:8][C:9]([C:11]2[S:15][C:14]([C:16]([NH:21][NH2:22])=[O:18])=[CH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(C(=O)NN2CCN(C)CC2)s1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(NC(=O)c2ccc(C(=O)NN)s2)CC1
Temperature: 25 °C
Yield: 65 %

Procedure:
Methyl 5-(4-methylpiperazin-1-ylcarbamoyl)thiophene-2-carboxylate (218 mg, 0.77 mmol) in ethanol (60 mL) was refluexed with heating with hydrazine monohydrate (0.40 mL) for 6 hours and allowed to cool to room temperature, and the solvent was evaporated at 40° C. mL of diethyl ether was added to the resulting oil, and the precipitated solid was collected by filtration, washed with water and dried to give 142 mg of the desired product (yield 65%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.ClC1N=C(N2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1>>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cncc(Cl)n1
Agent: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cncc(Cl)n2)CC1

Procedure:
tert-butyl 4-[(6-chloropyrazin-2-yl)amino]piperidine-1-carboxylate was prepared from 2,6-dichloropyrazine and tert-butyl 4-aminopiperidine-1-carboxylate using the conditions described for the preparation of tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1-carboxylate (Compound 1, Step 6). LRMS calculated for C14H21ClN4O2 [M+Na]+, 335.1; found 335.1.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].Cl.[Cl:7][C:8]1[CH:17]=[C:12]([C:13]([NH:15][OH:16])=[O:14])[C:11](O)=[CH:10][CH:9]=1.[OH-].[Na+]>O.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:5][CH:1]3[CH2:2][CH:3]([CH3:4])[O:16][N:15]3[C:13](=[O:14])[C:12]=2[CH:17]=1
Reactant: C/C=C/C=O
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1CC2Oc3ccc(Cl)cc3C(=O)N2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
400 ml. of tetrahydrofuran is combined with 100 gm. crotonaldehyde and placed in an ice bath. 125 gm. of hydrogen chloride are passed in at a temperature of about 20°-30° C. 182 gm. of 5-chlorosalicylhydroxamic acid is added in one portion and the reaction temperature is allowed to rise to about 31° C. The mixture is stirred at room temperature for about two hours and then 273 gm. of 50% w/w sodium hydroxide diluted with water to 600 ml. is dripped in. The reaction temperature is maintained from about 30° C. to about 40° C. during the alkali addition. When the addition is completed the mixture is heated to about 50° C. in vacuo for approximately one-half hour in order to remove as much tetrahydrofuran as possible. A solid precipitates which is diluted with 600 ml. of water, cooled, filtered and washed with excess water and pulled dry. The crude cake is returned to the reactor and dissolved in 900 ml. of boiling isopropanol, the solution is filtered hot and the reactor rinsed with 100 ml. hot isopropanol. The filtrate is cooled overnight to crystallize. The crystals are filtered, washed with isopropanol and dried at about 100° C. 134 gm. of 7-chloro-2-methyl-3,3a-dihydro-2H,9H-isoxazolo (3,2-b) (1,3) benzoxazin-9-one (m.p. 147° C.-151° C.) for a yield of 57.6% is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:7]([CH2:13][CH3:14])=[N:8][NH:9][C:10]=1[CH2:11][CH3:12].Cl.Cl[CH2:21][CH2:22][CH2:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[CH2:5][C:6]1[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH2:21][CH2:22][CH2:23][NH2:24])[C:7]=1[CH2:13][CH3:14]
Reactant: CCc1n[nH]c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: NCCCCl
Agent: Cl
Product: CCc1nn(CCCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Temperature: 150 °C
Yield: 84 %

Procedure:
The pyrazole of Example 11 (200 mg, 0.71 mmol) was mixed with 3-chloropropylamine hydrochloride (138 mg, 1.06 mmol). The resulting mixture was heated neat at 150° C., for 24 hours, under a nitrogen atmosphere. After cooling, the reaction mixture was partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogencarbonate solution (30 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0, by volume) gradually changing to dichloromethane:methanol:ammonia (90:10:1, by volume) to afford the title compound (203 mg) as a brown oil.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=2)[C:14]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:13]1.Br[CH2:37][C:38]#[N:39]>CN(C)C=O>[F:7][C:8]1[CH:9]=[C:10]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:21][CH2:37][C:38]#[N:39])[CH:19]=2)[C:14]([S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:13]1
Reactant: Nc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CCNc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 12 %

Procedure:
Cesium carbonate (3.8 g, 11.7 mmol) was added to an ice-cooled solution of 1-(3,5-difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indol-6-ylamine (Example 15a; 3.2 g, 7.79 mmol) in dry dimethyl formamide (15 ml). After 15 min. stirring, bromoacetonitrile (7.4 g, 62.3 mmol) was added and the reaction mixture was heated at 80° C. for 2 h. The mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (toluene/acetone 95:5) and crystallization from acetonitrile afforded the title compound (0.42 g). 1H-NMR (CDCl3) δ 8.27 (dd, 1H, J=8.4 and 1.6 Hz), 7.37 (d, 1H, J=8.6 Hz), 7.32 (s, 1H), 7.31 (ddd, 1H, J=8.4, 7.4 and 1.6 Hz), 7.19 (ddd, 1H, J=8.4, 7.4 and 1.6 Hz), 6.99 (dd, 1H, J=8.4 and 1.6 Hz), 6.76 (tt, 1H, J=8.6 and 2.0 Hz), 6.67 (m, 2H), 6.64 (dd, 1H, J=8.6 and 2.0 Hz), 6.54 (d, 1H, J=2.0 Hz), 5.32 (s, 2H), 4.13 (d, 2H, J=6.6 Hz), 4.04 (t, 1H, J=6.6 Hz).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NCC(C)C)C(C)C.S(Cl)([Cl:25])(=O)=O>C1(C)C=CC=CC=1>[Cl:25][C:10]1[CH:11]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: Oc1ccc(C2CCCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCCC2)cc1Cl
Temperature: 25 °C

Procedure:
A solution of 4-cyclopentylphenol (4 g) and diisobutylamine (0.35 mL) in toluene (75 mL) was heated to 70° C. with stirring. Sulfuryl chloride (2.0 mL) was introduced via syringe and the reaction stirred for 2 h at 70° C., then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resulting oil subjected to chromatography on silica gel using hexane/ethyl acetate eluent to afford the title compound (3.5 g). 1H NMR (400 MHz, CDCl3): δ7.19 (d, 1H, J=2.0 Hz); 7.06 (dd, 1H, J=2.2 Hz, 6.2 Hz); 6.94 (d, 1H, J=8.6 Hz); 5.37 (s, 1H); 2.92 (quint, 1H, J=7.0 Hz); 2.03 (m, 2H); 1.80 (m, 2H); 1.67 (m, 2H); 1.53 (m, 2H). MS: m/e=197(M+)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[N:4]=[N:3]1.Br[C:9]1[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=[C:13]([Br:15])[CH:14]=1>>[Br:15][C:13]1[CH:14]=[C:9]([NH:7][C:5]2[N:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[C:10](=[O:17])[N:11]([CH3:16])[CH:12]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cn1cc(N)nn1
Product: Cn1cc(Nc2cc(Br)cn(C)c2=O)nn1

Procedure:
Following the procedure in Example 148c, and starting with 149b (500 mg, 5.10 mmol, 1.0 eq.) and 3,5-dibromo-1-methylpyridin-2(1H)-one (2.04 g, 7.65 mmol, 1.5 eq.), 149c was obtained as a yellow solid (760 mg, 52%). MS-ESI: [M+H]+ 283.9.
Reaction SMILES: [F:1][C:2]([C:5]1[C:6](=[O:19])[C:7](N)=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3].Cl.N([O-])=[O:22].[Na+]>O>[F:1][C:2]([C:5]1[C:6](=[O:19])[C:7]([OH:22])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]=1[CH3:11])([F:4])[F:3]
Reactant: Cc1c(C(F)(F)F)c(=O)c(N)nn1-c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1c(C(F)(F)F)c(=O)c(O)nn1-c1ccccc1
Reaction time: 1 h
Yield: 89 %

Procedure:
A suspension of 1-m.trifluoromethylphenyl-1,4-dihydro-3-amino-4-oxo-6-methylpyridazine (21 grams, 0.078 mole) in 400 ml of water is chilled. After the addition of 12N hydrochloric acid (14.5 ml), sodium nitrite (5.38 g) is added, drop by drop, with 50ml of water. After agitation of the mixture for one hour at 0° C., two hours at 20° C., and then ten minutes at 50° C., it is rechilled, filtered through sintered glass, and washed with water. The precipitate is dissolved in 1200 ml of tepid ethyl acetate. After drying over sodium sulfate, filtration and evaporation under vacuum, the product crystallizes after being dissolved in diethyl ether. There is obtained, after recrystallization from a 75/25 mixture of dioxane and diethyl ether, the Compound 1 (18.75 grams; yield=90%).
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:4].C[Si](C)(C)C(CC1C=CC([N+]([O-])=O)=CC=1)C.[H][H]>[Pd]>[CH3:16][Si:2]([CH3:1])([CH3:15])[CH:3]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:4]
Reactant: CC(Cc1ccccc1[N+](=O)[O-])[Si](C)(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(Cc1ccc([N+](=O)[O-])cc1)[Si](C)(C)C
Product: CC(Cc1ccccc1N)[Si](C)(C)C

Procedure:
2-Trimethylsilyl-3-phenylpropene (2.5 g), prepared according to J. Org. Chem. 43, 147 (1978), was dissolved in THF and was then hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent yielded an oil (2.36 g) which was chromatographed on silica gel (eluent: hexane:ethylacetate 39:1) to give 2-trimethylsilyl-3-phenylpropane (2.3 g; 92.5% pure by NMR). This compound was dissolved in acetanhydride (4 ml), cooled to −35° C. and at this temperature a pre-cooled mixture of concentrated nitric acid (0.48 ml) and acetanhydride (2.4 ml) was added slowly. After warming to ambient temperature the reaction mixture was stirred for 3 hours and then poured into ice-cold diluted ammonia. After extraction with ethyl acetate and drying over sodium sulfate the solvent was removed and the residue was chromatographed on silica gel (eluent: hexane:TBF:ethylacetate 39:4:1) added) to yield a yellow oil (1.4 g) which consisted of an approximate 1:1 mixture of 2-trimethylsilyl-3-(2′-nitrophenyl)-propane and 2-trimethylsilyl-3-(4′-nitrophenyl)-propane. This mixture was hydrogenated over Pd on charcoal under atmospheric pressure and at room temperature until the uptake of hydrogen ceased. Removal of the catalyst and the solvent and chromatography on silica gel (eluent: hexane:ethyl acetate, 4:1) yielded 2-trimethylsilyl-3-(2′-aminophenyl)-propane (0.75 g; pure according to NMR). 0.15 g of this compound was dissolved in dry THF, cooled with ice and 2-chloronicotinoylchloride (0.13 g) was added, followed by pyridine (0.01 ml). The reaction mixture was stirred at room temperature over night, poured on to water and extracted twice with ethylacetate. The organic phase was washed with water, dried with sodium sulfate and the solvent was removed. Recrystallisation of the resulting crystals from hexane yielded Compound Number 9.35 (0.16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([OH:23])=O)[N:9]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:55]1[C:64]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59][C:58]=2[N:57]=[CH:56]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21]([N:61]3[CH2:62][CH2:63][C:64]4[S:55][CH:56]=[N:57][C:58]=4[CH2:59][CH2:60]3)=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: c1nc2c(s1)CCNCC2
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCc2ncsc2CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
32 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid was dissolved in 1.5 mL DMF. 32 mg HATU and 15 μL triethylamine were added to this solution and the mixture was stirred for 5 min. at RT. Then, 15 mg 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine and 15 μL triethylamine in 0.5 mL DMF were added. The mixture was stirred over night at RT. The reaction solution was purified by HPLC to yield 23 mg of the desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].F[C:23]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>CC1CCCO1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([O:15][C:23]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)nc1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1ccc(OCc2ccccc2)nc1
Temperature: 75 °C
Reaction time: 0.25 h

Procedure:
To 6-(benzyloxy)pyridin-3-ol (1.10 g) in 2-methyltetrahydrofuran (20 mL) was added potassium t-butoxide (5.47 mL, 1.0M in tetrahydrofuran). After stirring for 15 minutes, methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2 mL) was added and the reaction heated to 75° C. for 1 hour. The reaction was cooled, diluted with ethyl acetate (150 mL), washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (SF40-80 g) eluting with a gradient of 5% to 20% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[CH2:14][CH2:13]2)=[N:4]1.[CH3:27][C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>O1CCOCC1>[O:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:5]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH:26][C:28](=[O:29])[CH3:27])[CH2:22][CH2:21]3)[CH2:16][CH2:17]2)=[N:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1

Procedure:
A mixture in dioxane (5 ml) of trans-4-[2-(4-isoxazolo[4,5-c]pyridin-3-yl-piperazin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (100 mg, 0.25 mmol), AcOH (22 mg, 0.37 mmol), iPr2NEt (161 mg, 1.2 mmol) and TBTU (96 mg, 0.30 mmol) was stirred 16 h at r.t. After evaporation to dryness sat. aq. NaHCO3 was added and the product was extracted with 2 portions of CH2Cl2. The organic layers were directly loaded on a column. Flash chromatography (20 g SiO2, CH2Cl2/MeOH 100:0→90:10) yielded 62 mg (67%) of the title compound as white solid. m/z=372.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[C:16](=[C:17]([CH:22]=C)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)(=[O:12])=[O:11].I([O-])(=O)(=O)=[O:25].[Na+]>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([N:13]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:22]=[O:25])[C:16]=2[CH:15]=[CH:14]1)(=[O:12])=[O:11]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1cc(C)ccc1OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(C=O)cccc21
Reaction time: 0.5 h

Procedure:
OsO4 (10 mg, 0.05 mmol) was added to a stirred mixture of 1-[(2-methoxy-5-methylphenyl)sulfonyl]-4-vinyl-1H-indole (262 mg, 0.80 mmol; Intermediate 7) and 2,6-2,6-lutidine (186 μL, 0.46 mmol) in dioxane (9 mL). The mixture turned from colorless to black in 1 minute. Sodium periodate (0.684 g, 3.2 mmol) in water (3 mL, warmed to dissolve) was added. A grey precipitation was immediately formed. The mixture was stirred for 30 min. and partitioned between 2M aqueous HCl (25 mL) and DCM (25 mL). The organic layer was dried, filtered and concentrated to give the title compound (290 mg, 110%, still some dioxane according to HNMR) as a black solid. MS (ESI+) for C17H15NO4S m/z 330 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:17][C:18]1([CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]1[C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:27]([CH:19]1[C:18]([CH3:32])([CH3:17])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)C1Nc2ccccc2C1(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCCNC(=O)C1Nc2ccccc2C1(C)C
Reaction time: 3 h

Procedure:
Butylamine (15 ml) in toluene (40 ml) was cooled to −78° C. and a 2.5M solution of butyllithium in hexane (12.91 ml, 31.5 mmol) was added dropwise. After half an hour, ethyl 3,3-dimethylindoline-2(R/S)-carboxylate (4.600 g, 21 mmol) was added to the solution and this mixture was stirred under nitrogen for three hours. The mixture was then poured into a water/ice mixture (50 ml) and extracted with ethyl acetate; the extracts were dried over magnesium sulphate and the solvent was removed to give a brown oil. This was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent in order to give a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:27]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: CCOC(=O)c1cncc(-c2cc(OC)c(OC)c(OC)c2)c1

Procedure:
3,4,5-Trimethoxyphenylboronic acid (6.36 g) and ethyl 5-bromonicotinate (6.90 g) were reacted in the same manner as described in Preparation Example 1 to give the title compound.