Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:11]1[C:15](=[O:16])[CH2:14][CH:13]2[CH2:17][CH2:18][CH2:19][CH:12]12.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30]Br>C1COCC1>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][CH:14]1[C:15](=[O:16])[O:11][CH:12]2[CH2:19][CH2:18][CH2:17][CH:13]12
Reactant: O=C1CC2CCCC2O1
Reactant: BrCc1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1OC2CCCC2C1Cc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 8.7 ml of a 1 molar solution of lithium bis-(trimethylsilyl)-amide in THF are added dropwise to a solution, cooled to −78° C., of 1 g (7.9 mmol) of hexahydro-cyclopenta[b]furan-2-one in 20 ml of THF such that the temp. of the mixture does not exceed −65° C. After the addition has ended, stirring is continued at −78° C. for 10 min, and 1.93 g (8.7 mmol) of naphth-2-ylmethyl bromide are then added in one portion. Immediately afterwards, the cooling bath is removed and the mixture is allowed to warm to room temp. After 16 h of stirring at room temp., the mixture is taken up in water/diethyl ether and the aqueous phase is extracted twice with diethyl ether. The combined organic phases are dried over sodium sulphate and then concentrated. The residue is chromatographed over silica gel (mobile phase: dichloromethane); Yield: 1.2 g, colourless oil, diastereomer mixture: 87:13 (Example 1) 1H-NMR (200 MHz; [d6]-DMSO): δ[ppm]=1.2-1.9 (br m,7H), 2.6 (m,1H), 2.87 (dd, 1H); 2.93 (dd,1H), 4.72/4.75 (m;1H), 7.48-7.55 (m;3H), 7.76 (s;1H), 7.81-7.95 (m;3H).
Reaction SMILES: F[C:2]1([C:12]([F:15])([F:14])[F:13])[C:7](F)([F:8])[O:6]C(F)=C(F)[O:3]1.[F:16][C:17]([F:21])=[C:18]([F:20])[F:19]>FC(F)(C(F)(F)F)C(OOC(=O)C(F)(F)C(F)(F)F)=O.C(C(Cl)(F)F)(Cl)(Cl)F>[F:16][C:17]1([F:21])[C:18]([F:20])([F:19])[O:3][C:2]([C:12]([F:15])([F:14])[F:13])=[C:7]([F:8])[O:6]1
Reactant: FC1=C(F)OC(F)(C(F)(F)F)C(F)(F)O1
Reactant: FC(F)=C(F)F
Agent: O=C(OOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC1=C(C(F)(F)F)OC(F)(F)C(F)(F)O1
Reaction time: 0.03 h

Procedure:
A 240 mL s.s-lined tube was charged with 5.0 g (21 mol) of monomer 14, 50 mL of CFCl2CF2Cl, 5 mL of cold 3% perfluoropropionyl peroxide catalyst in CFCl2CF2Cl, and 30 g (0.30 mol) of tetrafluoroethylene. The tube was agitated as the mixture warmed; at 20° C. a rapid exotherm carried to 55° C. while the pressure fell to 0 psig. The solid, white polymeric product was heated under vacuum to constant weight, 29.2 g. Analysis of the volatiles by GC indicated the presence of about 1.5 g (30%) of recovered monomer 14. For the polymer, DSC on reheat showed a broad top, Tonset 271° C. Tpeak 297° C. TGA: 2% weight loss to 400° C., 3.5% weight loss to 440° C. Thus, copolymerization of 14 with TFE occurs readily to give very stable copolymer. A film pressed at 330° C. and 1800 psi for 2 min was clear and tough. ##STR36##
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([I:10])[N:4]2[N:3]=1.[CH2:11]([N:13]1[CH:17]=[C:16](B(O)O)[CH:15]=[N:14]1)[CH3:12].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([N:13]1[CH:17]=[C:16]([C:2]2[S:6][C:5]3=[N:7][CH:8]=[C:9]([I:10])[N:4]3[N:3]=2)[CH:15]=[N:14]1)[CH3:12]
Reactant: Brc1nn2c(I)cnc2s1
Reactant: CCn1cc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1cc(-c2nn3c(I)cnc3s2)cn1

Procedure:
A mixture of 2-bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole (0.18 g, 0.546 mmol, 1 eq), 1-ethyl-1H-pyrazole-4-boronic acid, pinacol ester (0.145 g, 0.655 mmol, 1.2 eq), Pd(PPh3)2Cl2 (0.077 g, 0.109 mmol, 0.2 eq) and 2M aq Na2CO3 (1 mL) in dioxane (3 mL) was refluxed for 2 h. The solvent was evaporated and the residue was treated with water. The suspension was filtered off (avoid taking the heavier reddish solid) and washed with water. The solid (110 mg) was used in the next step of the synthesis with no further treatment. HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.8 mL/min, 50° C.): tR=3.98 min, [M+H]+ m/z 345.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=O)[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:27][CH2:28][NH:29][C:30]([C:32]2[C:36]([CH3:37])=[C:35]([CH:38]=[C:15]3[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=5)[CH:13]=4)[NH:17][C:16]3=[O:21])[NH:34][C:33]=2[CH3:40])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(S(=O)(=O)Nc4cccc(Cl)c4)cc32)c(C)c1C(=O)NCCN1CCCC1
Yield: 69.5 %

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)amide (120 mg, 0.38 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (100 mg) to give 150 mg (69%) of the title compound as a yellow orange solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15](N(OC)C)=[O:16])[CH:11]=[CH:12][CH:13]=1.OS([O-])(=O)=O.[K+]>CCOCC.O1CCCC1.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH:15]=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)Cc1cccc(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of LiAlH4 (1.90 g, 51 mmol) in anhydrous ether (250 mL) was stirred at room temperature under nitrogen for about 1 hour. The suspension was cooled to about −45° C. To it was added drops of a solution of 2-(3-chlorophenyl)-N-methoxy-N-methyl-acetamide (8.19 g, 38.3 mmol, see Preparation 1) in 10 mL of anhydrous tetrahydrofuran (THF). The mixture was warmed to about 0° C. and stirred for about 3 hours. The solution was then cooled to about −45° C. To this solution was slowly added a solution of KHSO4 (13 g) in water (about 30 mL) the resulting mixture was filtered through CELITE®. The filtrate was concentrated in vacuo, the resulting solution was diluted with DCM and washed with 1N HCl aqueous solution (2 times), and brine (2 times) dried over anhydrous MgSO4, filtered and concentrated in vacuo. The title compound was obtained as a liquid (5.80 g), which was used immediately in the next step without further purification. Rf=0.71 (silica, EtOAc/hexane 1:3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][NH:8][CH:9]=1)=[O:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CCOCC>[O:15]=[C:13]1[C:7]2[NH:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1c[nH]cc1CCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
4-[4-(methoxycarbonyl)-1H-pyrrol-3-yl]butanoic acid (500 mg, 2.36 mmol) was dissolved in TFA (3 mL). TFAA (0.329 mL, 2.36 mmol) was added and the reaction was stirred at room temperature for 1 h. Organic solvent was evaportated to dryness and the residue suspended in Et2O (15 mL) and filrated to give 320 mg (yield: 64%) of the title compound as a light yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10](OS(C(F)(F)F)(=O)=O)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(C(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(N4CCN(C)CC4)ccc3c(C(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and 1-Methyl-piperazine to give 5 mg of [1-Isopropyl-6-(4-methyl-piperazin-1-yl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 365 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1>CN(C=O)C.CCOCC>[Si:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: N#CCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC#N)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a stirred solution of 4-hydroxybenzyl cyanide 77 (2.0 g, 15.0 mmol) in DMF (10 ml) was added t-butyldimethylsilyl chloride (2.5 g, 16.5 mmol). The reaction mixture was cooled to 0° C. and imidazole (2.3 g, 33.0 mmol) was added and then the mixture was allowed to warm to ambient temperature. After stirring for 3 hours, the reaction mixture was diluted with ether and washed with 0.5 M HCl, sat. aq. NaHCO3, water, and brine, then dried over MgSO4. The crude product was purified via flash SiO2 (eluted with hexane/ethyl acetate (8:1)) to give 78 as a clear oil (3.6 g, 98% yield). 1H-NMR (400 MHz, chloroform-d) δ7.87 (d, J=8.5 Hz, 2 H), 6.86 (d, J=8.5 Hz, 2 H), 3.54 (s, 2 H), 0.98 (s, 9 H), 0.23 (s, 6 H).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:24])[CH2:17]N1CCNCC1)[CH3:14]>O>[CH2:13]([O:15][C:16](=[O:24])[CH2:17][CH:7]1[CH2:6][CH2:5][N:4]([C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)[CH2:3][CH2:2]1)[CH3:14]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Solvent: O
Product: CCOC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2N)CC1
Temperature: 150 °C
Reaction time: 20 h
Yield: 154.5 %

Procedure:
A neat mixture of 0.500 g (2.54 mmol) of 3-amino-2-chloro-6-trifluoromethylpyridine and 0.870 g (5.09 mmol) of piperazin-1-yl-acetic acid ethyl ester is heated to 150° C. and stirred for 20 h. The mixture is cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic layer is washed with water followed by brine and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material is purified by flash silica gel chromatography to provide 0.650 g (77.1%) of (3′-amino-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>C1COCC1>[CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:7]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:29])[C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(=O)C(CN2C(=O)c3ccccc3C2=O)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide solution (1.8M in hexane, 6 ml, 10 mmol) was provided in absolute tetrahydrofuran (10 ml). The solution was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (1.1 g, 5 mmol), dissolved in dry THF (5 ml), was added in drops within 1 min. The batch was left for 30 min at −78° C. Then, N-(bromomethyl)phthalimide (3.6 ml, 15 mmol), dissolved in dry THF (20 ml), was added in drops within 1 min. The reaction mixture was stirred for 1 h at −78° C., then the cooling was removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with saturated NH4Cl solution (1×40 ml). The organic phases were then mixed with 1N HCl (50 ml) and thoroughly shaken out. The acid aqueous phase was separated and the organic phase was washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 2N NaOH (70 ml). An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. One of the two possible diastereoisomers of the ketone was isolated from the obtained residue (2 g) with a yield of 223 mg (12%) by means of chromatographic purification [silica gel 60 G (50 g); cyclohexane/ethyl acetate 1:10 (700 ml)].
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[N+](C1C=CC(S(O[CH2:27][C@H:28]2[CH2:30][C:29]2([F:32])[F:31])(=O)=O)=CC=1)([O-])=O>>[F:31][C:29]1([F:32])[CH2:30][C@@H:28]1[CH2:27][O:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=1
Reactant: CCOC(=O)c1ncc(O)cc1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CC2(F)F)cc1
Product: CCOC(=O)c1ncc(OC[C@H]2CC2(F)F)cc1F

Procedure:
Using ethyl 3-fluoro-5-hydroxypyridine-2-carboxylate and ((1R)-2,2-difluorocyclopropyl)methyl 4-nitrobenzenesulfonate, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]([NH:21][CH2:22][C:23]([O:25]C(C)(C)C)=[O:24])=[O:20]>ClCCl>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20]
Reactant: CC(C)(C)OC(=O)CNC(=O)OCCCNc1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNC(=O)OCCCNc1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 0.6 g of tert-butyl [3-(pyridin-2-ylamino)propoxycarbonylamino]acetate in 10 ml of dichloromethane. After the mixture has been stirred at room temperature for 1 hour, the solvent is distilled off, and the product is co-distilled with toluene, giving the free acid [3-(pyridin-2-ylamino)propoxycarbonylamino]acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[CH:17]2>>[NH:19]1[C:20]2[C:16](=[CH:15][C:14]([N:13]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[CH:22][CH:21]=2)[CH:17]=[N:18]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Product: Cc1ccc2c(c1)C(=Nc1ccc3[nH]ncc3c1)C(=O)N2
Yield: 60.1 %

Procedure:
The title compound (83 mg, 60%) was synthesized as a brown solid according to the method described for Example A74 using 5-methylisatin (80.5 mg, 0.5 mmol), 5-aminoindazole (66.5 mg, 0.5 mmol). 1H NMR indicated a 78:22 mixture of E/Z isomers. 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H, NH), 10.86 (s, 1H, NH), 8.08 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.8 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H) 6.33 (s, 1H), 1.89 (s, 3H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:23])[CH2:21]Cl)=[C:4]([F:24])[CH:3]=1.[CH2:25]([NH2:27])[CH3:26]>C(O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:23])[CH2:21][NH:27][CH2:25][CH3:26])=[C:4]([F:24])[CH:3]=1
Reactant: O=C(CCl)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Reactant: CCN
Solvent: CCO
Product: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-chloroacetamide (1.4 g) and 70% ethylamine (5 ml) in ethanol (25 ml) was heated at reflux for 3 hours and evaporated to dryness. The residue was processed to give a yellow solid (1.0 g). 1H NMR (CDCl3, TMS): 1.16(3H, t, J=7 Hz), 2.72(2H, q, J=7 Hz), 3.39(2H, s), 7.10(1H, dd, J=6,8 Hz), 7.26(1H, d, J=8 Hz), 8.00(1H, m), 8.24(1H, m), 8.45(1H, d, J=8 Hz), 9.86(1H, s).
Reaction SMILES: CC1C=CC(N)=CC=1N1C2N(N=C(C3C=NC=CC=3)C=2)C=C1.C(OC(NCCCOC1C=C(C=C(S(F)(F)(F)(F)F)C=1)C(O)=O)=O)(C)(C)C.[CH3:50][C:51]1[CH:56]=[CH:55][C:54]([NH:57][C:58]([C:60]2[CH:61]=[C:62]([CH:75]=[C:76]([S:78]([F:83])([F:82])([F:81])([F:80])[F:79])[CH:77]=2)[O:63][CH2:64][CH2:65][CH2:66][NH:67]C(=O)OC(C)(C)C)=[O:59])=[CH:53][C:52]=1[N:84]1[C:91]2[N:87]([N:88]=[C:89]([C:92]3[CH:93]=[N:94][CH:95]=[CH:96][CH:97]=3)[CH:90]=2)[CH:86]=[CH:85]1.Cl>O1CCOCC1.CO>[NH2:67][CH2:66][CH2:65][CH2:64][O:63][C:62]1[CH:61]=[C:60]([CH:77]=[C:76]([S:78]([F:80])([F:83])([F:82])([F:81])[F:79])[CH:75]=1)[C:58]([NH:57][C:54]1[CH:55]=[CH:56][C:51]([CH3:50])=[C:52]([N:84]2[C:91]3[N:87]([N:88]=[C:89]([C:92]4[CH:93]=[N:94][CH:95]=[CH:96][CH:97]=4)[CH:90]=3)[CH:86]=[CH:85]2)[CH:53]=1)=[O:59]
Reactant: Cc1ccc(NC(=O)c2cc(OCCCNC(=O)OC(C)(C)C)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: CC(C)(C)OC(=O)NCCCOc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(OCCCN)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)cc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 73 mg (0.17 mmol) of the compound of Example 30A were reacted and worked up analogously to the procedure of Example 16. In this manner, 118 mg (98% of theory) of the Boc-protected intermediate tert-butyl {3-[3-({4-methyl-3-[6-(pyridin-3-yl)-1H-imidazo[1,2-b]pyrazol-1-yl]phenyl}carbamoyl)-5-(pentafluoro-λ6-sulphanyl)phenoxy]propyl}carbamate were obtained. This compound was dissolved in 3 ml of 1,4-dioxane and 1 ml of methanol, 0.13 ml (0.52 mmol) of a 4 M solution of hydrogen chloride in 1,4-dioxane was added and the mixture was stirred at 80° C. for 1 h. The mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Method 18). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 41 mg (38% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[C:8]([N+:16]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>C(O)C.[Pd]>[NH2:16][C:8]1[CH:7]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:11]=[CH:10][C:9]=1[O:12][CH:13]([CH3:15])[CH3:14]
Reactant: CNS(=O)(=O)c1ccc(OC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CNS(=O)(=O)c1ccc(OC(C)C)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a mixture of N-methyl-4-[(1-methylethyl)oxy]-3-nitrobenzenesulfonamide (1.6 g, 5.8 mmol) in ethanol (20 mL) under nitrogen, Pd/C (0.160 g) was added. The flask was then evacuated and recharged with hydrogen three times. The resulting mixture was allowed to stir under a hydrogen atmosphere overnight at room temperature. The mixture was then filtered and concentrated to afford 3-amino-N-methyl-4-[(1-methylethyl)oxy]benzenesulfonamide (1.1 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.01-7.10 (m, 2H), 6.87-6.98 (m, 2H), 5.08 (br. s., 2H), 4.63 (dt, J=5.93, 11.98 Hz, 1H), 2.34-2.41 (m, 3H), 1.29 (d, J=6.02 Hz, 6H); MS (m/z) 244.7 (M+H+)
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[C:17]1([Si:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][Si:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]1
Yield: 60.3 %

Procedure:
The title compound was synthesised following a similar procedure as described for Example 11. 3′-Fluoro-2′,3′-dideoxyuridine (0.214 g, 0.93 mmol) was reacted with triphenylsilyl chloride (0.332 g, 1.12 mmol) in dry pyridine (7 mL) for 3 h. to yield the title compound as a white solid (0.274 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[CH:11]([CH:13]=O)=O>C1COCC1.O>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[C:4]([N:5]=1)=[N:9][CH:11]=[CH:13][N:10]=2
Reactant: Nc1nc(Cl)cc(Cl)c1N
Reactant: O=CC=O
Solvent: O
Solvent: C1CCOC1
Product: Clc1cc(Cl)c2nccnc2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4.81 g (27 mmol) 4,6-dichloro-pyridine-2,3-diamine (synthesis described in J. E. Schelling, C. A. Salemink, Rec. Tray. Chim. Pays-Bas 91, 650 [1972]) in 50 ml THF was treated with 5.22 g (27 mmol) of a 30% solution of glyoxal in water and the mixture was stirred for 3 days at room temperature. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and diluted sodium carbonate solution. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent yielding 6,8-dichloro-pyrido[2,3-b]pyrazine as off-white fine needles; HPLC/MS (B): 1.93 min, [M+H] 200.
Reaction SMILES: [CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20].Cl>N1C=CC=CC=1.ClCCl.C(OCC)(=O)C>[CH2:1]([N:4]1[C@@H:13]2[C@H:8]([C:9]3[CH:17]=[CH:16][C:15]([NH:18][S:28]([C:25]4[CH:26]=[CH:27][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:23][CH:24]=4)(=[O:30])=[O:29])=[CH:14][C:10]=3[CH2:11][CH2:12]2)[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCC[C@H]2c3ccc(N)cc3CC[C@@H]21
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCN1CCC[C@H]2c3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3CC[C@@H]21
Temperature: 5 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
(4aS,10bS)-4-Allyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-8-ylamine (60 mg, 0.23 mmol) was dissolved in pyridine-dichloromethane (1:2, 7.5 mL) and cooled to 5° C. 4-Isopropylbenzenesulfonyl chloride (50 mg, 0.24 mmol) was added and the solution stirred at 5° C. for 3 h. Solution was evaporated, partitioned between ethyl acetate and water, and the organic phase separated and dried over MgSO4. The filtered solution was concentrated and separated by column chromatography (dichloromethane-3% MeOH) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (20 mg, 15%).