Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH:29]=[CH:28]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:36]([C:32]4[CH:31]=[C:30]5[C:35](=[CH:34][CH:33]=4)[N:27]([CH3:26])[CH:28]=[CH:29]5)(=[O:37])=[O:38])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cn1ccc2cc(S(=O)(=O)Cl)ccc21
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc5c(ccn5C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1-methyl-1H-indole-5-sulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Cl.[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:24]C)[CH:5]=[CH:6]2.[BrH:26]>>[BrH:26].[O:2]1[C@:14]2([CH3:20])[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:22][CH3:23])[CH2:11][CH2:12][C:13]2=[O:21])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([OH:24])[CH:5]=[CH:6]2
Reactant: COc1ccc2c3c1O[C@@]1(C)C(=O)CC[C@@]4(OC)[C@@H](C2)NCC[C@]314
Agent: Br
Agent: Cl
Product: CO[C@@]12CCC(=O)[C@]3(C)Oc4c(O)ccc5c4[C@@]31CCN[C@@H]2C5
Yield: 66 %

Procedure:
A solution of 4,5α-epoxy-3,14-dimethoxy-5-methylmorphinan-6-one hydrochloride (H. Schlnidhammer et al., Helv. Chim. Acta Vol. 77: 1585-1589, 1994) (1.0 g, 2.73 mmol) in 3.5 ml of 48% HBr was refluxed for 15 min. After cooling, the now brown solution was evaporated, the residue treated with MeOH and again evaporated (this operation was repeated once). The oily residue was crystallized from MeOH to yield 713 mg (66%) of colorless 4,5a-epoxy-3-hydroxy-14-methoxy-5-methylmorphinan-6-one hydrobromide (compound 6). M.p.>230° C. (dec.). IR (KBr): 3545 and 3495 (+NH, OH), 1720 (CO)cm-1. CI-MS:m/z 316(M+ +1). 1H-NMR(DMSO-d6):δ9.37 (s, OH), 8.65 (broad s, +NH2), 6.64 (dd, J=8.2, 8.2 Hz, 2 arom. H), 3.36 (s, OCH3 --C(14)), 1.48 (s, CH3 --C(5)). Analysis calculated for C18H21NO4. HBr. MeOH(428.33):C 53.28, H 6.12, N 3.27; found: C 53.12, H 5.97, N 3.32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:9].Cl.O>N1C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:20])(=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1)[CH3:9]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A stirred solution of 2-aminopyridine (282 mg, 3.0 mmol) in dry pyridine (5.0 mL) was treated with (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (prepared according to the procedure of Kawashima et. al, as described in Chem. Pharm. Bull. 1995, 43(7), 1132) dropwise at 0–5° C. under argon. Upon completion of addition, the reaction was slowly warmed to 25° C. The reaction was stirred at 25° C. until no starting materials remained. At this time, the reaction was cooled to 0° C. and was acidified to pH=5 with a 1.0M aqueous hydrochloric acid solution. The reaction mixture was poured into water and was extracted with ethyl acetate. The combined organic extracts were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/97 methanol/methylene chloride) afforded [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid ethyl ester (0.26 g, 27%) as a colorless solid; 1H NMR (CDCl3, 300 MHz) δH 13.67 (broad s, 1H), 8.30 (dd, J=5.9, 1.1 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.65 (tt, J=8.1, 1.7 Hz, 1H), 7.50–7.30 (m, 3H), 6.77 (t, J=6.3 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.22 (t, J=7.0 Hz, 3H); LRMS for C15H16N2O4S (M+H)+ at m/z=321.
Reaction SMILES: Cl.[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.C(Cl)Cl.[OH:34][CH:35]([CH2:40][CH3:41])[C:36]([O:38][CH3:39])=[O:37].C(N(CC)CC)C>CCOCC>[F:2][C:3]([F:30])([F:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([O:34][CH:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH3:41])=[O:25])=[CH:22][CH:21]=1
Reactant: CCC(O)C(=O)OC
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 10.0 g. 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 200 ml. methylene chloride is added dropwise a solution of 3 g. methyl α-hydroxybutyrate and 5 g. triethylamine in 100 ml. ether. After 17 hours stirring at room temperature, the precipitate is collected and washed with several portions of ether. The ether solution is washed with water, dried and evaporated to yield the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[C:7]([CH3:24])=[C:8]([N:13]3[C:21](=O)[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]3=O)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1>C(O)C>[CH3:1][C:2]1([CH3:25])[CH2:6][C:5]2[C:7]([CH3:24])=[C:8]([N:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:21]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2
Solvent: CCO
Product: Cc1c(C)c(N2Cc3ccccc3C2)c(C)c2c1OC(C)(C)C2
Yield: 84 %

Procedure:
By using 2-[2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1H-isoindole-1,3(2H)-dione, the title compound was synthesized according to Example 2a. Yield: 84%. Melting point: 161-163° C. (Ethanol).
Reaction SMILES: [F:1][C:2]1([F:18])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>C(O)C>[C:22]([CH2:21][CH2:20][C:19]([O:9][CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[C:2]([F:1])([F:18])[C@@H:6]1[OH:7])=[O:25])([OH:24])=[O:23]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Solvent: CCO
Product: Nc1ccn([C@@H]2O[C@H](COC(=O)CCC(=O)O)[C@@H](O)C2(F)F)c(=O)n1

Procedure:
Dry 2'-deoxy-2',2'-difluorocytidine (311 mg) was added to dry ethanol and brought to reflux. Succinic anhydride (2.5 g) was added in portions over a half hour period and the mixture was refluxed an additional 1/2 hour. The mixture was concentrated in vacuo and the resulting crude product was placed on a silica gel column and eluted with a step gradient of 5%, 20%, and 50% methanol in methylene chloride. The desired product was isolated in the 50% methanol in methylene chloride wash and contained 148 mg of material. This product was combined with product from a similar experiment providing a total of 253 mg of material. This material was taken up in 8 ml of 0.01M ammonium acetate solution. The pH was adjusted with ammonium hydroxide to 8.6 and the solution placed on a freshly packed mono-Q anion exchange column (Pharmacia Inc., 800 Centennial Avenue, Piscataway, N.J. 08854). Desired fractions were combined, frozen, and lyophilized. The residue was dissolved in distilled water, frozen, and lyophilized several more times, then dissolved in a small amount of methanol and benzene, frozen, and lyophilized providing 60 mg of the desired title product. The proton NMR spectra was consistent with the structure of the desired product:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([CH3:43])[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:27][N:26](COCC[Si](C)(C)C)[C:23]4=[N:24][CH:25]=3)[CH:15]=2)[CH2:10]1)(C)(C)C.C(Cl)(=O)C>CO>[NH2:7][CH2:8][C:9]1([CH3:43])[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:20]3[N:21]=[C:22]4[C:28]([C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:27][NH:26][C:23]4=[N:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:10]1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCN(c2cccc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c2)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: CC1(CN)CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
1-{2-[3-(3-Aminomethyl-3-methyl-pyrrolidin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following a similar procedure but using (1-{3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-3-methyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester as starting material. In this instance the starting material was taken into a 4/1 mixture of MeOH and acetyl chloride and the reaction mixture was stirred at RT for 2 hours before being evaporated. The residue was taken into 2 mL of concentrated HCl and stirred at RT for 1 hour before being diluted with H2O and neutralized by addition of solid NaOH. The product was obtained in 44% yield after SiO2 chromatography (DCM/[DCM/MeOH/NH4OH 60/10/1] 100-60% DCM).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>ClCCl.C(O)C>[Cl:3][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cnn2cccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn2cccc2c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 86454.6 %

Procedure:
To POCl3 (225 mL, 2.42 mmol) at 0° C. was added ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (50 g, 0.242 mmol) and the mixture was stirred until complete dissolution. At this time, triethylamine (36.8 mL, 0.266 mmol) was added dropwise and the resulting mixture was heated to 110° C. and allowed to stir for ˜16 h. The resulting mixture was allowed to cool and the POCl3 was removed in vacuo to afford a dark brown residue. This material was dissolved in dichloromethane and was cooled to 0° C. and diluted with 375 mL of ethanol. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The ethanol was removed under vacuum and the resulting semi-solid was dissolved in dichloromethane and stirred with 10% aqueous NaHCO3 for 1 h. The mixture was filtered through celite and the phases were separated. The aqueous portion was extracted with additional dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4, decanted and the solvent was removed under vacuum to give the crude product. The crude material was purified by flash silica gel column chromatography to yield 47 g (86%) of a solid as the title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 1.43 (t, J=7.2, 6.8 Hz, 3 H), 4.43 (q, J=7.2, 6.8 Hz, 2 H), 6.940-6.99 (m, 2H), 7.84 (q, J=0.8, 1.6 Hz, 1 H), 8.51 (s, 1H)). 13C-NMR (400 MHz, DMS-d6) ppm: 163.30, 141.89, 138.16, 124.86, 120.69, 114.99, 109.90, 105.22, 61.55, 14.21. LCMS (conditions A): m/z 225. HPLC (condition B): Retention time=3.47 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Yield: 25.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.5 g, 14.6 mmol) and SOCl2 (2.7 mL, 36.4 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.1 mL, 29.1 mmol) and CHCl2 (75 mL). The product chromatographed in CH2Cl2 is to provide 1.05 g of a yellow orange solid (26%). 1H NMR (CDCl3) δ: 8.54 (d, J=8.1 Hz, 1H); 8.30 (br s, 1H); 7.41 (dd, J=1.5, 8.0 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.10 (t, J=8.1 Hz, 1H); 7.09 (dt, J=1.6, 7.8 Hz, 1H); 6.78 (dd, J=0.4, 7.9 Hz, 1H); 6.63 (dd, J=0.9, 8.2 Hz, 1H); 4.69 (br s, 2H). MS (ES): m/z 303.0 (M+22), 281.0 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH3:30])=[C:28]([C:31]([OH:33])=O)[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[C:73]([NH:76][NH2:77])(=[O:75])[CH3:74].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]([CH3:30])=[C:28]([C:31]([NH:77][NH:76][C:73](=[O:75])[CH3:74])=[O:33])[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)NN
Reactant: Cc1c(C(=O)O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NNC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 12 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (120 mg, 0.23 mmol), HBTU (130.9 mg, 0.345 mmol) and HOAt (46.97 mg, 0.345 mmol) in dry DMF (15 mL) is added a solution of acetic hydrazide (34.09 mg, 0.46 mmol) and diisopropylethylamine (121 ul, 0.693 mmol) in dry DMF (5 mL). The reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is purified by preparative HPLC to give 4-{6-[6-(N′-Acetyl-hydrazinocarbonyl)-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (120 mg, 75.4%). [M+H]+=578.32.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[C:6]1[S:7][C:8]2[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([Cl:16])[C:9]=2[N:10]=1.[Cl-].[NH4+]>C(OCC)C.Cl[Ni](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>[Cl:16][C:11]1[C:9]2[N:10]=[C:6]([CH2:1][CH3:2])[S:7][C:8]=2[CH:14]=[C:13]([F:15])[CH:12]=1
Reactant: CC[Mg]Br
Reactant: Fc1cc(Cl)c2nc(Cl)sc2c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1nc2c(Cl)cc(F)cc2s1
Reaction time: 2 h

Procedure:
A solution of 0.2 mol of ethyl magnesium bromide in diethyl ether was added to a solution of 22.0 g (0.1 mol) of 2,4-dichloro-6-fluorobenzothiazole and 3.3 g (5 mmol) of dichlorobis(triphenylphosphine)nickel in 0.5 1 of diethyl ether. Stirring was carried out for 2 hours, after which the mixture was poured onto saturated aqueous ammonium chloride solution. The product was extracted with diethyl ether. The combined organic phases were washed with water, dried over magnesium sulfate and finally evaporated down. Purification of the crude product was effected by means of silica gel chromatography (eluent: 8:2 cyclohexane/methyl tert-butyl ether). Yield: 10.3 g.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N+](C1C=CC=CC=1)([O-])=O.S(Cl)(Cl)=O.[CH3:23][C:24]1[CH:32]=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1>Cl>[CH3:23][C:24]1[C:32]([C:1](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=2)=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1
Reactant: Cc1cc2ccccn2n1
Reactant: O=C(O)c1cccnc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1nn2ccccc2c1C(=O)c1cccnc1
Temperature: 0 °C

Procedure:
To a mixture of 107 g of nicotinic acid and 315 ml of nitrobenzene were added dropwise whilst stirring 107 g of thionyl chloride, the mixture was warmed for one hour at a temperature of 160°-180° C. The reaction mixture was allowed to cool, then 35 g of 2-methylpyrazolo[1,5-a]pyridine was introduced in one portion, and the mixture was heated to 140°-160° C. for 2 hours, and poured into 1 l of ice water. Next, 50 ml of concentrated hydrochloric acid were added. This solution was extracted twice with 500 ml of benzene. After neutralizing with potassium carbonate, the aqueous layer was extracted with chloroform, the extract was dried with anhydrous Na2SO4 and after removal of the chloroform, the residue was chromatographed over SiO2 employing CH2Cl2 --AcOEt (3:2) mixture as eluent. The eluate was evaporated to dryness in vacuo and the residue was recrystallized (EtOH-Hexane); yield 30 g (46%), mp 89°-90° C.
Reaction SMILES: [CH3:1][CH:2]([OH:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][CH:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: CC(O)c1ccc(F)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A solution of alpha-methyl-4-fluorobenzyl alcohol (0.7 ml; 5.5 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (220 mg; 5.5 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (765 mg, 5.5 mmol) in dimethylformamide was chilled to 0° C., and activated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.1 g of 2-fluoro-6-[1-(4-flurophenyl)-ethoxy]-benzonitrile (78% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]1)=O)(C)(C)C.[ClH:25]>CO>[ClH:25].[ClH:25].[C:19]1([CH2:18][CH2:17][CH2:16][N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC1CCCN(CCCc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: NCC1CCCN(CCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 50 ml of methanol was dissolved 8.902 g of N-tert-butoxycarbonyl-[1-(3-phenylpropan-1-yl)piperidin-3-ylmethyl]amine, followed by addition of 10 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 3 hours. This reaction mixture was concentrated to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([C:10]2[S:11][CH2:12]CN=2)[N:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]=[C:29]=[O:30])(=[O:27])=[O:26])=[O:18]>C(#N)C>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:28][C:29]([NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH2:10][S:11][C:12]2[S:11][CH2:10][CH2:4][N:3]=2)[N:3]=1)=[O:30])(=[O:26])=[O:27])=[O:18]
Reactant: COc1cc(C2=NCCS2)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(CSC2=NCCS2)cc(OC)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
7.0 g of 2-amino-4-methoxy-6-(4,5-dihydrothiazol-2-yl)-pyrimidine are suspended in 50 ml of abs. acetonitrile, and 6.6 g of 2-methoxycarbonylphenylsulfonylisocyanate are added. There is formed a clear solution with heating, and the product subsequently precipitates in crystalline form. After the reaction mixture has been stirred for 3 hours at 20 °-25° C., it is cooled to 0° C. and the solid substance is separated. There is thus obtained N-(2-methoxycarbonylphenyl-sulfonyl)-N'-[4-methoxy-6-(4,5-dihydrothiazon-2-yl)-thiomethyl-pyrimidin-2-yl]-urea, m.p. 135°-145° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 0.25 h
Yield: 85 %

Procedure:
5-Bromoindole (3.92 g; 20 mmol) was dissolved in DCM (100 mL) and DMF (1 mL). NaH (0.88 g, 22 mmol; 60% in oil) was added to the cooled solution. After stirring for 15 minutes, triisopropylsilyl chloride (3.86 g, 20 mmol) was added dropwise to the reaction mixture. After 3 h, water (1 mL) was added, followed by MgSO4. The mixture was filtered and concentrated and the residue put through a silica column with hexane as eluent. The product was obtained as a pale yellow oil (5.96 g, 17 mmol; yield 85%). 1H NMR (CDCl3) δ 1.13 (18H, d, J=8), 1.67 (3H, m), 6.55 (1H, d, J=3), 7.21 (1H, dd, J=9, 2), 7.24 (1H, J=3), 7.36 (1H, d, J=9) and 7.74 (1H, d, J=2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](B(O)O)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1CCc2cc(Br)ccc2N1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Product: O=C1CCc2cc(-c3cccnc3)ccc2N1
Temperature: 100 °C

Procedure:
A sealable tube containing 6-bromo-3,4-dihydroquinolin-2(1H)-one (0.10 g, 0.44 mmol), 3-pyridylboronic acid (0.56 g, 4.6 mmol), bis(di-tert-butyl(4-dimethylamino phenyl)phosphine)dichloropalladium(II) (6.3 mg, 8.9 μmol), and potassium carbonate (0.18 g, 1.3 mmol) was flushed with nitrogen before tert-butanol (4.9 mL) and water (0.6 mL) were added. The tube was flushed again with nitrogen, sealed tightly and heated to 100° C. overnight. The reaction was then cooled to room temperature, poured into saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-15% methanol in ethyl acetate) provided the title compound: LCMS m/z 225.27 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.77 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 8.06 (ddd, J=1.7, 2.0, 8.1 Hz, 1H), 7.52 (s, 1H), 7.50-7.47 (m, 2H), 6.99 (d, J=8.1 Hz, 1H), 3.05 (t, J=7.5, 7.7 Hz, 2H), 2.61 (t, J=7.5, 7.7 Hz, 2H).