Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH:3]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1.O.[OH-].[Li+].Cl>C(O)(=O)C.O>[Br:1][C:3]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([C:17]([OH:19])=[O:18])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)c1cc(C2CCC2)nc(C(F)(F)F)n1
Reactant: BrBr
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(C2(Br)CCC2)nc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
Bromine (0.13 mL, 2.6 mmol) was added to a solution of ethyl 6-cyclobutyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.65 g, 2.4 mmol, from Step B) in acetic acid (2.0 mL) and the reaction was heated to 80° C. for one hour. The mixture was concentrated and the resulting oil was dissolved in THF (8.0 mL) and cooled to 0° C. A solution of lithium hydroxide, monohydrate (0.20 g, 4.7 mmol) in water (2.0 mL) was added. After stirring for 20 minutes, 1N HCl was added to achieve pH 4. Additional water was introduced and the product was extracted with six portions of 10% isopropanol in chloroform. The combined extracts were dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification (0.64 g, 80%). H NMR (400 MHz, dmso) δ 8.27 (s, 1H), 3.17-2.97 (m, 2H), 2.92-2.71 (m, 2H), 2.34 (dtt, J=10.9, 9.1, 6.9 Hz, 1H), 1.84 (dtt, J=11.0, 8.6, 5.6 Hz, 1H); LCMS (M+H)+: 324.9, 326.7.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:20].O>C1COCC1>[ClH:20].[N:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCC2)CC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl trans-4-(pyrrolidin-1-yl)cyclohexylcarbamate (399 mg, 1.44 mmol) in THF (12 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was heated at 65° C. for 18 ht. The reaction mixture was cooled and concentrated to afford the desired product (350 mg, >99%) as an off-white solid: ESI MS m/z 169 [C10H20N2+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:15])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[F:15][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]=[CH:12]2
Reactant: CCOC(=O)c1ccc(F)c2occc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(F)c2occc12
Temperature: 55 °C

Procedure:
A mixture of 7-fluoro-benzofuran-4-carboxylic acid ethyl ester (1.54 mmol) and NaOH (2.31 mmol) in MeOH (1.7 mL) and water (1.7 mL) is heated to 55° C. for 90 min. The mixture is concentrated vacuo and made acidic by addition of aq. HCl (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H NMR (DMSO-d6): δ=13.19 (bs, 1H); 8.25 (s, 1H); 7.89-7.94 (m, 1H); 7.41 (s, 1H); 7.36 (t, J=9.5 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[CH:1]1([C:4]([C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CC(O)(c1ccc2c(c1)OCCO2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc4c(c3)OCCO4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.82 mmol) of the compound from Example 142A and 0.17 ml (2.18 mmol) of trifluoroacetic acid were added to 322 mg (1.82 mmol) of the compound from Example 8A in 3 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and by recrystallization from acetonitrile. 184 mg (27% of theory) of the title compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:11][C:9]2[N:10]=[C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]3[N:8]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1cccn2nc(N)nc12
Product: Cc1cccn2nc(Nc3ccc(S(C)(=O)=O)cc3)nc12

Procedure:
(4-Methanesulfonyl-phenyl)-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (500 mg, 3.37 mmol) and 1-bromo-4-methanesulfonyl-benzene (973 mg, 1.23 mmol) in a manner analogous to Example 2d. Product was isolated as an off-white solid (0.369 g, 36%). MP=227-230° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.35 (s, 1H), 8.67 (d, J=6.9 Hz, 1H), 7.88 (d, J=8.9 Hz, 2H), 7.82 (d, J=8.9 Hz, 2H), 7.42 (d, J=7.1 Hz, 1HO, 6.99 (dd, J=7.1 Hz, 7.1 Hz, 1H), 3.14 (s, 3H). MS=303 (MH)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.ClCCl>[OH-].[Na+]>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1c(C(F)(F)F)nc2ccccc2c1O

Procedure:
A suspension of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 h. After cooling, dichloromethane was added and the aqueous phase was separated and acidified with concentrated HCl to pH 4. The resulting precipitate was collected via filtration, washed with water and Et2O to provide 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80%). 1H NMR (DMSO-d6) δ 8.18-8.21 (d, J=7.8 Hz, 1H), 7.92 -7.94 (d, J=8.4 Hz, 1 H), 7.79-7.83 (t, J=14.4 Hz, 1H), 7.50-7.53 (t, J=15 Hz, 1H); ESI-MS 257.0 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].[OH-].[Na+].Cl.[NH:19]1[CH2:24][CH2:23][C:22](O)([OH:25])[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: OC1(O)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)N2CCC(=O)CC2)cc1C(F)(F)F
Yield: 91.7 %

Procedure:
A solution of 4-methoxy-3-(trifluoromethyl)benzoyl chloride (4.00 g, 16.8 mmol) in toluene (16 mL) and a solution of NaOH (3.8 mL of 4.0 M, 15 mmol) were contemporaneously added drop-wise to a solution of piperidine-4,4-diol hydrochloride (2.30 g, 15.2 mmol) in NaOH (7.6 mL of 2.0 M, 15 mmol) at 25° C. The mixture was stirred for 90 min before the toluene was removed in vacuo. The alkaline phase was extracted with dichloromethane (3 times). The organics were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo to provide 1-(4-methoxy-3-(trifluoromethyl)benzoyl)piperidin-4-one (4.2 g, 91%). ESI-MS m/z calc. 301.3. found 302.2 (M+1)+. Retention time: 0.95 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J=1.9 Hz, 1H), 7.70 (dd, J=8.6, 2.1 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 4H), 2.55 (s, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CNCCc1ccccn1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCc4ccccn4)c3)nc12
Temperature: 140 °C
Yield: 70.5 %

Procedure:
A stirred suspension of 200 mg (0.45 mmol) 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide, 1.23 ml (8.90 mmol) 2-(2-methylaminoethyl)pyridine and 290 mg (0.89 mmol) cesium carbonate in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with dichloromethane, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (0/100-2.5/97.5 methanol/dichlormoethane) followed by trituration in ether afforded 160 mg (71%) N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-2-[methyl-(2-pyridin-2-yl-ethyl)-amino]-isonicotinamide as a light yellow crystalline solid. ES-MS m/e (%): 505 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34][CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][NH:38]C(OC(C)(C)C)=O)=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49]>C(Cl)Cl>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:25]4[C:24](=[O:26])[CH2:23][C:22]([CH3:28])([CH3:27])[CH2:21][C:20]=4[NH:19][C:18]4[NH:29][N:30]=[C:31]([C:32]([O:34][CH2:35][C:36]([CH3:47])([CH3:46])[CH2:37][NH2:38])=[O:33])[C:17]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)COC(=O)c1n[nH]c2c1C(/C=C/c1ccc(-c3cccc(F)c3)cn1)C1=C(CC(C)(C)CC1=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CN)COC(=O)c1n[nH]c2c1C(/C=C/c1ccc(-c3cccc(F)c3)cn1)C1=C(CC(C)(C)CC1=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 mg of 3-tert-butoxycarbonylamino-2,2-dimethylpropyl 4-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]vinyl}-7,7-dimethyl-5-oxo-4,5,6,7,8,9-hexahydro-1H-pyrazolo[3,4-b]quinoline-3-carboxylate are dissolved in DCM (2.5 ml), admixed with TFA (2.5 ml) and stirred at RT for 3 h. The solvent is removed under reduced pressure, and the residue is suspended in toluene and concentrated by rotary evaporation once again. Yield: 63 mg; LC/MS (method J): m/z=543 (M+1); Rt=0.680 min
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10].F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].O>C(#N)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:3][C:4]1[S:5][C:6]([CH3:11])=[CH:7][C:8]=1[C:9]#[N:10])([O-:21])=[O:20]
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
Potassium hydroxide (101.4 g) in acetonitrile (150 ml) is taken under nitrogen and cooled to 0-5° C. A solution of 2-amino-5-methylthiophene-3-carbonitrile (100 g) and o-fluoronitrobenzene (122.6 g) in acetonitrile (550 ml) is added. The reaction is then stirred for 3 hours and chilled water is added. The solid thus obtained is filtered off and air-dried. The solid is crystallized from water-methanol mixture and the crystallized solid is dried under vacuum at 40-45° C. to obtain the title compound (140 g).
Reaction SMILES: C(OC(=O)[N:7]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH2:45])[C:8]1[CH:13]=[C:12]([N:14]([CH3:38])[C:15]([N:17]([C:26]2[C:31]([Cl:32])=[C:30]([O:33][CH3:34])[CH:29]=[C:28]([O:35][CH3:36])[C:27]=2[Cl:37])COCC[Si](C)(C)C)=[O:16])[N:11]=[CH:10][N:9]=1)(C)(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[C:62](O)(=[O:66])[C:63]#[C:64][CH3:65].O>C(Cl)Cl>[Cl:37][C:27]1[C:28]([O:35][CH3:36])=[CH:29][C:30]([O:33][CH3:34])=[C:31]([Cl:32])[C:26]=1[NH:17][C:15](=[O:16])[N:14]([C:12]1[N:11]=[CH:10][N:9]=[C:8]([NH:7][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[NH:45][C:62](=[O:66])[C:63]#[C:64][CH3:65])[CH:13]=1)[CH3:38]
Reactant: CC#CC(=O)O
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccccc3N)ncn2)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC#CC(=O)Nc1ccccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of (2-amino-phenyl)-{6-[3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-methyl-3-(2-trimethylsilanyl-ethoxymethyl)-ureido]-pyrimidin-4-yl}-carbamic acid tert-butyl ester (50 g, 0.075 mmol) and DCC (42 g, 0.2 mmol) in DCM (50 mL) was added a solution of but-2-ynoic acid (13 g, 0.15 mmol) in DCM (10 mL) at 0° C., and the resulting mixture was stirred at room temperature overnight. Water (1 mL) was added to quench the reaction. The mixture was concentrated and the residue was purified by reverse phase chromatography to obtain the title compound (20 mg, yield: 34%). MS (ESI): 659 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][Cl:17])[C:10]2=[O:18])=[N:6][N:5]=1)[CH:2]=[CH2:3].[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH2:1]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][CH3:19])[CH2:13][CH2:12][N:11]([CH2:16][Cl:17])[C:10]2=[O:18])=[N:6][N:5]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=CCc1nnc(N2C(=O)N(CCl)CCC2O)s1
Solvent: CO
Product: C=CCc1nnc(N2C(=O)N(CCl)CCC2OC)s1

Procedure:
Tetrahydro-1-(5-allyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-allyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)(=[O:13])=[O:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH4+].[Cl-]>CO.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([CH3:23])[CH:15]=2)(=[O:12])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(S(=O)(=O)c2ccc([N+](=O)[O-])c(C)c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)cc(S(=O)(=O)c2ccc(N)c(C)c2)c1
Yield: 93.1 %

Procedure:
0.29 g (0.00086 mol) of 1-(3,5-dimethoxyphenylsulphonyl)-3-methyl-4-nitrobenzene was suspended in a mixture of 10 ml of methanol and 10 ml of water, treated with 0.30 g of iron powder and 0.30 g of NH4Cl and heated at reflux for 1.5 hrs. After cooling the mixture was diluted with 50 ml of methanol, treated in an ultrasound bath for a short time and suction filtered. The filter material was washed with a large amount of methanol and the filtrate was concentrated. The residue was suspended in water and treated in an ultrasound bath. The precipitate which thereby resulted was filtered off under suction and chromatographed on silica gel with ethyl acetate/hexane 1:1. There was obtained 0.246 g (92.5%) of 4-(3,5-dimethoxybenzenesulphonyl)-2-methyl-phenylamine as yellow coloured crystals; m.p.: 121-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)[CH3:2].C([Sn]([N:52]=[N+:53]=[N-:54])(CCCC)CCCC)CCC.C(O)(C(F)(F)F)=O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:54][N:53]=[N:52][N:14]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(-c2nnn[nH]2)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from above (0.260 g, 0.51 mmol) and tributyltin azide (4 equiv., 2.0 mmol, 0.650 g) were dissolved in DMSO (2 mL) and the solution stirred at 80° C. for 48 h. The reaction was then quenched with 1 N HCl (10 mL) and stirred for an additional 40 min. The aqueous phase was decanted and the oily residue dissolved in DMSO and purified by reversed-phase HPLC using 0.1% TFA—0.1% TFA in acetonitrile gradients to give after lyophilisation, the TFA salt of the title compound as a white amorphous solid (97 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:25]([CH3:28])([CH3:27])[CH3:26])(=O)=O>C1(C)C=CC=CC=1>[CH3:26][Si:25]([N:9]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]#[N:2])=[CH:5][CH:6]=1)[Si:25]([CH3:28])([CH3:27])[CH3:26])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N(Cc1ccc(C#N)cc1)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.2 %

Procedure:
About 5.20 g of 4-(aminomethyl)benzonitrile hydrochloride, 10.30 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 15.1 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 3 days to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding 4-[bis(trimethylsilyl)aminomethyl]benzonitrile (4-BTMSAMBZN) as a white solid (8.12 g, 95% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 7.00 (doublet, 2H, aromatic protons), 6.83 (doublet, 2H, aromatic protons), 3.72 (singlet, 2H, CH2 protons), −0.06 (singlet, 18H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.5 %

Procedure:
A mixture of 56 g of 4-nitrophenol, 90 g of methyl bromoacetate, 100 g of potassium carbonate and 500 ml of dimethylformamide was stirred at room temperature for 2 days. At the end of this time, the solvent was removed by distillation under reduced pressure. The resulting residue was mixed with water and the aqueous mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was triturated with hexane to give 63.3 g of the title compound, melting at 98°-99° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19])=[O:4].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]2[N:9]3[CH:20]=[N:21][CH:22]=[C:8]3[CH:7]=[N:6][C:5]=2[C:3]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:4])=[C:13]([F:19])[CH:14]=1
Reactant: C=COCCON
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a stirred solution of 5-(4-bromo-2-fluoro-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (150 mg, 0.41 mmol) and O-(2-vinyloxy-ethyl)hydroxylamine (127 mg, 1.23 mmol, 3.0 eq) in anhydrous THF (7.5 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.23 mmol, 3.0 eq.), and the reaction mixture was stirred at room temperature. After 1 h the reaction mixture was quenched with saturated aqueous solution of sodium bicarbonate and diluted with ethyl acetate. The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 5% methanol in dichoromethane) to give an oil. Crystallization from DCM—ether—hexane afforded the desired product as a pale orange solid (160.2 mg, 89.4%). LCMS (method C): RT=2.53 min, [M+H]+=437/439.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([NH2:14])=[N:11][C:12]=2[CH3:13])[CH2:3][CH2:2]1.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:14][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:12]([CH3:13])[N:11]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(N)ccc1COCC1CC1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Product: Cc1nc(NS(=O)(=O)c2cccc(Cl)c2C)ccc1COCC1CC1

Procedure:
This material was prepared in analogy to example 1 from 5-cyclopropylmethoxymethyl-6-methyl-pyridin-2-ylamine (0.053 g) and 3-chloro-2-methyl-benzenesulfonyl chloride (0.058 g) as a light brown solid (0.046 g). MS (ESI−): 379.1 ([M−H]−)