Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=C[CH:2]=1.C([N:10]1[C:14]([NH2:15])=[N:13][C:12]([S:16]([NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])(=[O:18])=[O:17])=[N:11]1)(=O)C.[H-].[Na+].CI>CN(C)C=O>[NH2:15][C:14]1[NH:10][N:11]=[C:12]([S:16]([N:19]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])[CH3:2])(=[O:18])=[O:17])[N:13]=1
Reactant: c1ccncc1
Reactant: CC(=O)n1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(c1c(Cl)cccc1Cl)S(=O)(=O)c1n[nH]c(N)n1
Reaction time: 0.5 h

Procedure:
9.80 g (22.8 mmol) of the pyridine salt of 1-acetyl-5-amino-N-(2,6-dichlorophenyl)-1,2,4-triazole-3-sulphonamide was dissolved in 300 ml dimethylformamide and 0.89 g (29.7 mmol) 80% sodium hydride added portionwise at room temperature. The mixture was stirred for a further 30 minutes and 1.7 ml (27.8 mmol) methyl iodide added. The mixture was allowed to stand overnight and concentrated. The residue was taken up in 2N aqueous sodium hydroxide and made slightly acidic by addition of 3N hydrochloric acid. The crystals were separated, washed with water and ether and recrystallised from acetonitrile.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5[CH2:41][CH2:40][CH2:39]O5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1CCC[C@H:47]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:37]1([CH2:36][NH:35][CH2:34][C:32]2[CH:33]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])[CH2:14][CH2:15]3)[CH:29]=[C:30]([F:42])[CH:31]=2)[CH2:47][CH2:39][CH2:40][CH2:41]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNCC5CCCC5)c4)cc23)CC1
Yield: 37.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-cyclopentylmethanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 21.6 mg of the title compound (37.9%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][C:14]2=[O:21])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:24][O:19][C:18]([CH:16]1[CH2:17][N:13]([C:5]2[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=2)[C:14](=[O:21])[CH2:15]1)=[O:20]
Reactant: O=C(O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CC(=O)N(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 20 °C
Reaction time: 17 h
Yield: 1357.3 %

Procedure:
8.8 g (0.025 mole) of the 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid produced according to Example 1 is refluxed together with 0.3 g of p-toluenesulphonic acid in 130 ml of absolute methanol, and the reaction mixture is kept at this temperature during 17 hours. It is subsequently cooled to 20° C and 0.1 g of sodium carbonate is added. Excess methanol is evaporated off. The residue is dissolved in diethyl ether, extracted three times with water, dried, and concentrated by evaporation. By recrystallisation from n-hexane there is obtained 8.4 g (91% of theory) of 1-(3,5-bis-trifluoromethylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid methyl ester; m.p. 68°-70° C. Analysis for C14H11F6NO3 (molar weight 355.17):
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]Br.O>C1COCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3]
Reactant: COc1ccccc1CCCCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1CCCCOCCCCCCBr
Yield: 288.4 %

Procedure:
NaH (46% dispersion in oil; 1.36 g) was added portionwise to a solution of 2-methoxybenzenbutanol (5.0 g) and 1,6-dibromohexane (1.38 g) in THF (50 ml). The suspension was refluxed for 20 h and was treated cautiously with H2O (20 ml). The resulting emulsion was extracted with ER (2×50 ml) and the dried extract was evaporated to leave a yellow oil. The oil was purified on a column of silica (Merck 5385, 600 ml) [A] to give the title compound as a colorless oil (5.6 g). T.l.c. [B] Rf 0.2.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH2:9][CH2:10][CH3:11].[NH2:14][C:15]1[S:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][N:19]=1>ClCCl>[CH:20]([C:17]1[S:16][C:15]([NH:14][C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[N:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: CC(C)c1cnc(N)s1
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ncc(C(C)C)s1
Temperature: -5 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
Triethylamine (0.97 ml; 6.34 mmol) and butanoyl chloride (0.52 ml; 5.07 mmol) were added in this order to a solution of 2-amino-5-isopropyl-1,3-thiazole (0.6 g; 4.23 mmol) in dichloromethane (8 ml), cooled to −5° C. The reaction mixture was stirred at −5° C. for 2 hours and then warmed to room temperature. After additional 4 hours, the organic layer was washed with water, saturated sodium bicarbonate, 1N hydrochloric acid, brine, dried over sodium sulfate and evaporated. The residue was recrystallized from cyclohexane to yield 0.45 g (50%) of the title compound as a colourless solid (m.p. 95–97° C.)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]4)[CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.CC([NH:41][C:42]([NH2:44])=[O:43])(C)C>>[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:15]2[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[CH:6][N:7]=[C:2]([NH:41][C:42]([NH2:44])=[O:43])[CH:3]=4)[NH:8][N:9]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)C1
Reactant: CC(C)(C)NC(N)=O
Product: NC(=O)Nc1cc2c(-c3cccc(N4CCC[C@H](N)C4)n3)n[nH]c2cn1
Yield: 23 %

Procedure:
Following the Buchwald-Hartwig procedure of Example 224, tert-butyl (3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and (1,1-dimethylethyl)urea were reacted and deprotected by the procedure of Example 229. The mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 20 mg (23%) of 298 over three steps. ESI MS m/z 353.2 (M+1). 1H NMR (400 MHz, DMSO): 9.14 (s, 1H), 8.96 (s, 1H), 8.75 (s, 1H), 8.40 (s, 2H), 7.63 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 6.48 (s, 2H), 4.92 (d, J=11.4 Hz, 1H), 4.05 (d, J=12.9 Hz, 1H), 3.09 (m, 1H), 2.94-2.77 (m, 2H), 2.54 (s, 2H), 2.05 (d, J=9.7 Hz, 1H), 1.84 (d, J=13.1, Hz, 1H), 1.64-1.42 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1Cl)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][N:35]=1)[C:30](O)=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][N:35]=[C:27]([C:26]([F:37])([F:25])[F:36])[CH:28]=5)[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1ccnc(C(F)(F)F)c1
Yield: 70.5 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (103 mg, 0.30 mmol), 2-(trifluoromethyl)isonicotinic acid (86 mg, 0.45 mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and N,N-dimethylformamide (3.0 mL) as starting materials and in the same manner as in Example 106, the title compound (102 mg, 71%) was obtained as a light blue powder.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].[Si:23](Cl)([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[CH2:13]([O:17][C:18]([O:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)COC(=O)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)=C(OCC(C)C)O[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Step 1 To a solution of diisopropylamine (2.94 mL, 20.8 mmol) in THF (20 mL) under nitrogen at 0° C. was added nBuLi (2.5M in hexanes, 8.32 mL, 20.8 mmol, 1 eq.) and the solution stirred at 0° C. for 30 min. The solution was cooled to −78° C. and then a solution of isobutylisobutyrate (3.49 mL, 20.8 mmol) in THF (6 mL) was added dropwise and then the reaction stirred at −78° C. for 1 h. TMS-Cl (3.19 mL, 25 mmol) was then added dropwise and the reaction allowed to warm to room temperature over 3 h. The reaction was quenched with ice-water (20 mL) and EtOAc (20 mL) was added. The organic phase was washed with water (10 mL) and then brine (10 mL) before it was dried (MgSO4), filtered and concentrated to give (1-isobutoxy-2-methyl-propenyloxy)-trimethyl-silane (3.5 g) used crude in the next reaction.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][NH:8][C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.O>CN(C)C=O>[C:1]([C:5]1[N:6]=[CH:7][N:8]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:22])[F:23])=[CH:16][N:15]=2)[C:9]=1[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]cnc1C(C)(C)C
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(C)(C)C)ncn1-c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.33 h

Procedure:
To a solution of 0.5 g (3.6 m mol) of 4-tert-butyl-5-methylimidazole in 5 ml of N,N-dimethyl formamide is added slowly 150 mg (3.7 m mol) of an oily sodium hydride (60%) while cooling with ice, followed by stirring at the same temperature for 20 minutes. After the reaction is completed, to the reaction mixture is added dropwise 0.71 g (3.6 m mol) of 2,3-dichloro-5-trifluoromethylpyridine, followed by stirring at room temperature for 9 hours. After the reaction is completed, the reacton mixture is poured into water, and extracted with ethyl acetate. Further, then the residue is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained product is subjected to silica gel chromatography to give 4-tert-butyl-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-methylimidazole.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:35]([CH:33]4[CH2:32][CH2:31][C:30](=[O:29])[NH:34]4)=[O:36])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)C1CCC(=O)N1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495. Found: [M+H]+ 496.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][N:25]1[CH:29]=[C:28]([C:30]2[CH:31]=[C:32]([C:36]3[N:41]=[CH:40][C:39]([C:42]4[CH:43]=[N:44][NH:45][CH:46]=4)=[CH:38][N:37]=3)[CH:33]=[CH:34][CH:35]=2)[CH:27]=[N:26]1>CC(N(C)C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][N:44]2[CH:43]=[C:42]([C:39]3[CH:38]=[N:37][C:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([C:28]5[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=5)[CH:31]=4)=[N:41][CH:40]=3)[CH:46]=[N:45]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cn[nH]c4)cn3)c2)cn1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cccc(-c3ncc(-c4cnn(CC5CN(C(=O)OC(C)(C)C)C5)c4)cn3)c2)cn1
Yield: 131.9 %

Procedure:
A solution of 3-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester (Matrix scientific, 200 mg; 0.68 mmol; 1.0 eq.), cesium carbonate (442 mg; 1.36 mmol; 2.0 eq.) and 2-[3-(1-methyl-1H-pyrazol-4-yl)phenyl]-5-(1H-pyrazol-4-yl)pyrimidine (example 3, 205 mg; 0.68 mmol; 1.0 eq.) in dry DMA (3 mL) was heated at 100° C. O/N. The reaction mixture was then diluted with water and extracted with EtOAc (three times). Combined organic phases were washed with brine (three times), dried over magnesium sulfate, filtered and concentrated. The crude was dissolved in DMSO and precipitated by addition of acetonitrile. It was filtered, rinced with acetonitrile and dried under vacuum to give the title compound as a yellow powder (423 mg, quantitative). MS (ESI+): 472.3.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[C:18]2=[C:24]([C:27]([OH:29])=O)[N:25]=[CH:26][N:17]2[C:16]2[CH:30]=[CH:31][S:32][C:15]1=2.N>CN(C)C=O>[O:13]=[C:14]1[N:20]2[CH2:21][CH2:22][CH2:23][C@H:19]2[C:18]2=[C:24]([C:27]([NH2:3])=[O:29])[N:25]=[CH:26][N:17]2[C:16]2[CH:30]=[CH:31][S:32][C:15]1=2
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 25 °C
Yield: 91.3 %

Procedure:
12.33 g (76 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 22 g (76 mmol) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid (EP 59 390 A1) in 100 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. Subsequently, the solution was cooled to room temperature and 14 ml of aqueous ammonia solution were added dropwise thereto. After a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 20 g (91%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxamide as colourless crystals of m.p. 222°-223°.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17](O)([CH3:19])[CH3:18]>>[ClH:1].[CH:17]([O:7][C:6](=[O:8])[C@H:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(=O)O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)[C@H](O)[C@@H](N)CC1CCCCC1

Procedure:
Hydrogen chloride was passed into a suspension of 1.0 g of (2R, 3S)-3-amino-4-cyclohexyl-2-hydroxy butyric acid hydrochloride in 10 ml of isopropyl alcohol with stirring under ice-cooling, and the mixture was heated under reflux for 2 hours. After evaporation of the reaction mixture, benzene was added to the residue and the mixture was evaporated under reduced pressure. The residue was dissolved in 10 ml of ethyl acetate and the precipitated crystals were collected by filtration to obtain 1.0 g of (2R, 3S)3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester hydrochloride as a white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[CH:10]=[N:11][C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 5.47 g of 5-[6-(hydroxymethyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 2.57 g of methanesulfonyl chloride, and 2.39 g of triethylamine in 130 ml dichloromethane give [3-(5-carbamoyl-4-{1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-3H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:14]=[CH:13][C:12]=2[NH:22]C(=O)OC(C)(C)C)=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:31][P:32]1(=[O:43])[O:37][CH2:36][C:35]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:34][O:33]1.CCN(C(C)C)C(C)C>CS(C)=O>[NH2:22][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:5]1[CH:4]=[CH:3][C:2]([N:40]2[CH2:41][CH2:42][C:35]3([CH2:34][O:33][P:32]([CH3:31])(=[O:43])[O:37][CH2:36]3)[CH2:38][CH2:39]2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(Cl)nc1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)OCC2(CCN(c3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cn3)CC2)CO1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
tert-Butyl [2-{[(6-chloropyridin-3-yl)carbonyl]amino}-4-(2-thienyl)phenyl]-carbamate (150 mg, 0.35 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (169 mg, 0.70 mmol), and DIEA (183 μL, 1.05 mmol) were combined in DMSO (4 mL) and stirred at 90° C. for 24 h. The mixture was directly purified by reverse phase HPLC (35-90% MeCN/water w/0.025% TFA) to afford the desired product as a yellow solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The resulting residue was purified by reverse phase HPLC (10-70% MeCN/water w/0.025% TFA). Fractions containing the product were diluted with saturated NaHCO3 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to give the desired product as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.48 (d, J=3.3, 1H), 8.72 (t, J=2.7 Hz, 1H), 8.08-8.05 (m, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.33 (dd, J=4.9, 0.9 Hz, 1H), 7.26 (dt, J=8.4, 1.7 Hz, 1H), 7.22 (dd, J=3.6, 1.2 Hz, 1H), 7.02 (dd, J=5.0, 3.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.51 (dd, J=8.9, 6.0 Hz, 1H), 5.10 (s, 2H), 4.15-3.97 (m, 3H), 3.93-3.82 (m, 1H), 3.62-3.50 (m, 3H), 3.36-3.28 (m, 1H), 2.06-1.98 (m, 1H), 1.93-1.80 (m, 3H), 1.50 (d, J=17.4 Hz, 1.5H), 1.49 (d, J=17.4 Hz, 1.5H). MS: cal'd 499 (MH+), exp 499 (MH+).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[Cl:38]C1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:38].[F:29][C:26]([F:27])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1
Reactant: Fc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccccc2C(F)(F)F)cc1
Reactant: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Agent: Cl
Product: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Yield: 55 %

Procedure:
This material was prepared from 1-benzhydryl-3-[2-(trifluoromethyl)-4′-fluorobenzyloxy]azetidine (161) (7.5 mmol) using the procedure described for compound (9). Crystallisation from DIPE-MeOH afforded the product as a white solid (1.49 g, 55%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][NH:12][CH:13]=[C:9]3[C:8](=[O:14])[N:7]([CH3:15])[C:6]2=[O:16])[CH2:3][CH2:2]1.[Br:17]N1C(=O)CCC1=O.O>ClCCCl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][C:13]1[NH:12][N:11]=[C:10]2[C:9]=1[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]2[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: Cn1c(=O)c2c[nH]nc2n(CC2CC2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Solvent: O
Product: Cn1c(=O)c2c(Br)[nH]nc2n(CC2CC2)c1=O
Yield: 82.2 %

Procedure:
7-(Cyclopropylmethyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (6.0 g), N-bromosuccinimide (7.8 g), and 100 mg of AIBN was taken up in 50 mL of 1,2-dichloroethane. The heterogeneous mixture was brought to reflux overnight. Water (100 mL) was added to the solution and separated. The organic layer was dried over sodium sulfate, filtered and removed under reduced pressure to give a yellow solid. The compound was flashed through a plug of silica gel, gave 6.7 g of white powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13](Cl)(=[O:15])=[O:14])=[CH:3]1.[CH3:17][NH2:18]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([S:13]([NH:18][CH3:17])(=[O:15])=[O:14])=[CH:3]1
Reactant: CN
Reactant: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccccc21
Product: CNS(=O)(=O)c1cn(C)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride (3.56 g) and aqueous methylamine (30% w/v; 100 ml) was stirred at room temperature for 1 hour. The precipitated solid was filtered off, washed with water and crystallised from aqueous acetic acid to give the compound 1,N-dimethyl-4-oxo-1,4-dihydroquinoline-3-sulphonamide, m.p. 248°-250°.