Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].[CH:37](N(C(C)C)CC)(C)C.CO.C[Si](C=[N+]=[N-])(C)C>C(#N)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([O:11][CH3:37])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: CCc1cc2c(OC)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), diisopropylethylamine (0.72 mL), methanol (2 mL) and acetonitrile (18 mL) was added trimethylsilyldiazomethane (2M hexane solution, 0.72 mL), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with water and ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.28 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH:13]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:10][O:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][O:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(NS(=O)(=O)c2ccccc2[N+](=O)[O-])CO1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)CO1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A solution of 4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic acid tert-butyl ester (694 mg, 1.86 mmol) and PhSH (0.142 ml, 1.1 equiv) in MeCN (10 ml) under argon at room temperature was treated with K2CO3 (386 mg, 1.5 equiv). The reaction mixture turned bright yellow. The reaction was left to stir overnight. As TLC indicated complete consumption of starting material, volatiles were removed in vacuo. Flash column chromatography eluting with dichloromethane:methanol (10/0 then 9/1) afforded 336 mg of the title amine (1.8 mmol, 96%). 1H-NMR (CDCl3, 400 MHz): 4.03-3.92 (m, 3H), 3.89-3.76 (m, 1H), 3.70 (dd, 1H), 3.37 (dd, 1H), 1.51 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C.C(Cl)Cl>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCN4CCOCC4)CC3)noc2c1

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2O3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131-132° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:12]([N:15]([CH3:29])[C@@H:16]2[CH2:24][CH2:23][CH2:22][C:21]3[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]2=3)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C>CS(C)=O>[CH3:29][N:15]([S:12]([C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:3]=1)(=[O:13])=[O:14])[C@@H:16]1[CH2:24][CH2:23][CH2:22][C:21]2[N:20]([CH2:25][C:26]([OH:28])=[O:27])[N:19]=[CH:18][C:17]1=2
Reactant: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CN([C@@H]1CCCc2c1cnn2CC(=O)O)S(=O)(=O)c1cc(N2CCCC2)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 46.7 %

Procedure:
{(R)-4-[(3-Fluoro-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (25 mg, 0.066 mmol) and pyrrolidine (47 mg, 0.66 mmol) were dissolved in dimethyl sulfoxide (1.5 mL). The mixture was heated in a microwave oven at 180° C. for 50 minutes. The resulting mixture was acidified with acetic acid to pH 4, and then filtered and purified by preparative HPLC to afford {(R)-4-[methyl-(3-pyrrolidin-1-yl-5-trifluoromethyl-benzenesulfonyl)-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (15 mg, 48.5%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 7.24 (s, 1 H), 7.14 (s, 1 H), 6.98 (s, 1 H), 6.41 (s, 1 H), 5.05 (t, 1 H), 4.75 (s, 2 H), 3.35 (t, 4 H), 2.61 (s, 3 H), 2.45 (m, 2 H), 2.08-1.61 (m, 8 H). MS calcd. for C21H25F3N4O4S 486, obsd. (ESI+) [(M+H)+] 487.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH:34]1([N:40]=[C:41]=[O:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:41]([NH:40][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:42])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)NC4CCCCC4)c3C2=O)C(=O)N1
Reaction time: 0.33 h
Yield: 48.5 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, cyclohexyl isocyanate (0.35 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2:EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(cyclohexylamino)carboxamide (0.37 g, 49%) as a white solid: mp 208-210° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.34 (t, J=5.8 Hz, 1H), 6.04 (d, J=7.9 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.4 Hz, 1H), 4.62 (d, J=5.8 Hz, 2H), 3.37 (m, 1H), 2.96-2.83 (m, 1H), 2.63-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.76-1.02 (m, 10H); 13C NMR (DMSO-d6) δ 172.78, 169.84, 167.59, 167.04, 157.28, 141.13, 134.64, 133.42, 131.51, 126.98, 121.64, 48.82, 47.91, 38.66, 33.23, 30.94, 25.27, 24.47, 21.99; Anal. Calcd. For C21H24N4O5: C, 61.16; H, 5.87; N, 13.58. Found: C, 61.21; H, 5.79; N, 13.63.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:7](F)[CH:8]=2)[N:3]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[CH3:28][S:25]([C:21]1[CH:20]=[C:19]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:33]4[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Reactant: Nc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3c2)c1
Temperature: 95 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine (0.06 g, 0.00015 mol), (2-aminopyrimidin-5-yl)boronic acid (0.03 g, 0.00023 mol), cesium carbonate (0.097 g, 0.0003 mol), DMF (5 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.005 g, 0.0000075 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mixture was cooled and water was added. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 0-5% methanol in chloroform) to provide the desired product (0.05 g, 7%). 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 2H), 8.36 (s, 1H), 8.25 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.21 (s, 2H), 3.85 (s, 8H); 1H NMR (400 MHz, DMSO-d6+D2O): δ 9.12 (s, 2H), 8.20 (s, 1H), 8.14-8.06 (m, 3H), 7.95 (d, J=7.6 Hz, 1H), 7.79 (t, J=7.2 Hz, 2H), 3.83-3.77 (m, 8H), 3.21 (s, 3H). LC-MS (ESI): Calculated mass: 462.1; Observed mass [M+H]+: 463.1 (RT=0.23 min).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C@H:9]1[C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([C@H:13]2[CH2:14][CH2:15][NH:8][C@@H:9]2[C:10]([OH:12])=[O:11])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CCCCC2)[C@H]1C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1NCC[C@@H]1C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of N-BOC-3(R)-cyclohexyl-(L)-proline from step A (1.0 g, 0.28 mmol) in CH2Cl2 (3 mL) at 0° C. was added TFA (6 mL). The reaction was allowed to warm to rt for 4 h. The reaction was then concentrated in vacuo and azeotroped with toluene. The crude product was used in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]=1[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1.[CH2:38]([Mg]Br)[CH3:39]>C1COCC1>[C:21]([O:20][C:18]([N:16]1[CH2:17][CH:14]([C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:25][CH3:26])[C:3]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[C:2]3[Cl:1])([OH:13])[CH2:38][CH3:39])[CH2:15]1)=[O:19])([CH3:22])([CH3:24])[CH3:23]
Reactant: COc1nc2ccc(C(=O)C3CN(C(=O)OC(C)(C)C)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2nc(OC)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1)C1CN(C(=O)OC(C)(C)C)C1

Procedure:
To a flask containing tert-butyl-3-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline-6-carbonyl)azetidine-1-carboxylate (250 mg, 0.47 mmol, Intermediate 13: step b) was added THF (8 mL) to give a homogeneous solution. The solution was cooled in an ice-water bath and ethylmagnesium bromide (3 M in Et2O, 0.3 mL, 0.9 mmol) was introduced. After 35 minutes the reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc, (4×30 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness to afford a colorless gum. Chromatography on silica gel (5% EtOAc-DCM increasing to 1% MeOH-DCM) provided the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.60 (dd, J=8.7, 2.1 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 4.35 (s, 2H), 4.16-4.08 (m, 1H), 4.07 (s, 3H), 4.00 (t, J=8.5 Hz, 1H), 3.71-3.53 (m, 2H), 3.20-3.07 (m, 1H), 2.13 (s, 1H), 1.97-1.74 (m, 2H), 1.41 (s, 9H), 0.73 (t, J=7.4 Hz, 3H); MS (ESI): mass calcd. for C29H32ClF3N2O4, 564.2, m/z found 565.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=1.Cl.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:11][CH2:12][N:13]([C:2]2[C:7]([C:8]#[N:9])=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:14]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: N#Cc1nccnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1nccnc1N1CCc2ccccc2CC1

Procedure:
In analogy to the procedure as described in example 12 the 2-chloro-3-cyanopyrazine (J. Chem. Soc., Perkin Trans. 1 1991, 11, 2877-81) was treated with 2,3,4,5-tetrahydro-1 H-benzo[d]azepine hydrochloride (J. Heterocycl. Chem. 1971, 8(5), 779-83) and N-ethyl-diisopropylamine in N,N-dimethylformamide at room temperature followed by 60° C. to yield the 3-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-pyrazine-2-carbonitrile as light yellow solid; MS: 251 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=1.[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.CC(=O)OCC>CCCCCC>[CH:15]1([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][CH3:30])(=[O:28])=[O:27])=[CH:22][C:21]=2[C:2]2[C:7]3[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=3[C:5](=[O:13])[N:4]([CH3:14])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: Cn1cc(Br)c2c(c1=O)NC(=O)CO2
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2OCC(=O)N3)c1

Procedure:
The title compound of step 2 was reacted with 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 224, step 5. Silica gel chromatography (40-100% EA in hexane over 8 min) gave the title compound. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.27-0.33 (m, 2H) 0.51-0.57 (m, 2H) 1.11 (t, J=7.33 Hz, 3H) 1.14-1.22 (m, 1H, partially obscured) 3.22-3.28 (m, 2H) 3.51 (s, 3H) 3.96 (d, J=7.07 Hz, 2H) 4.54 (s, 2H) 7.27 (d, J=8.84 Hz, 1H) 7.52 (s, 1H) 7.67 (d, J=2.02 Hz, 1H) 7.79-7.92 (m, 1H) 10.10 (s, 1H) LCMS: 419 (M+H)+
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>ClCCl.[Cl-].[Na+].O>[Br:31][CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc(CO)s1
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(CBr)s1
Reaction time: 2 h
Yield: 72.5 %

Procedure:
To a stirred solution of 2-hydroxymethyl-5-nitro-thiophene (18.8 g, 118 mmol) in dichloromethane (500 ml) at 0° C. was added triphenylphosphine (3 1.5 g, 120 mmol) followed by carbon tetrabromide (39 g, 118 mmol). The mixture was stirred for 2 hours, poured into half saturated brine and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent removed at reduced pressure. The crude product was purified by silica gel chromatography using 15% ethyl acetate/hexane as the eluant to give 2-bromomethyl-5-nitrothiophene (19 g, 61%) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O([CH2:29][C:30]([F:33])([F:32])[F:31])S(C(F)(F)F)(=O)=O.ClCCl>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:29][C:30]([F:33])([F:32])[F:31])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2N(CC(F)(F)F)C1=O

Procedure:
In an analogous manner to that described in Example 53 a), the alkylation of the (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester with 2,2,2-trifluoroethyl triflate, yielded, after chromatography on silica gel using a 99:1-mixture of dichloromethane and methanol as the eluent, the title compound as a white foam; MS: m/e=360 (M+H)+.
Reaction SMILES: C(O[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[CH:9]=1)=O)(=O)C.[F:21][C:22]([F:33])([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([C:6]2[N:27]=[C:25]([C:24]3[C:23]([C:22]([F:32])([F:21])[F:33])=[N:31][CH:30]=[CH:29][CH:28]=3)[O:26][CH:5]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)COC(C)=O)cc([N+](=O)[O-])c1OC
Reactant: NC(=O)c1cccnc1C(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1cc(-c2coc(-c3cccnc3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 mL) were added 2-(trifluoromethyl)nicotinamide (3.135 g, 16.5 mmol) and boron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and the dried over anhydrous magnesium sulphate, filtered and evaporated. The pure 4-(3,4-dimethoxy-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)oxazole was obtained by column chromatography over silica gel (petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.488 g (42%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])[C:3]=1[C:23]#[N:24].Cl.[CH3:26][NH:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([C:3]1[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:14]([NH:16][O:17][CH3:18])=[O:15])=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[N:27]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:26])#[N:24]
Reactant: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(Cl)c2C#N)c1
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)c1ccc(C)c(Nc2nc(SC)nc(N(C)CC(C)(C)C)c2C#N)c1
Yield: 44.4 %

Procedure:
3-(6-Chloro-5-cyano-2-methylsulfanyl-pyrimidin-4-ylamino)-N-methoxy-4-methyl-benzamide (3.33 g, 9.2 mmol), N-methyl-neopentylamine hydrochloride (2.05 g, 15 mmol) and DIEA (3.87 g, 30 mmol) in THF (10 mL) were heated to 60° C. for overnight. The solvent was removed in vacuo and the product (1.75 g) was obtained after purification by silica gel column chromatography.
Reaction SMILES: C(OC(=O)CC[C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[CH2:22]([O:25]C1C=CC(C#N)=CC=1)[CH2:23][CH3:24]>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:11]=[CH:10][C:9]([O:25][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Reactant: CCCOc1ccc(C#N)cc1
Product: CCCOc1ccc(C(=N)NO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-propoxy-benzonitrile; LC-MS: tR=0.71*min, [M+1]+=195.28.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].O.[NH2:14][NH2:15]>C(O)CO>[CH3:9][O:8][C:6]1[CH:7]=[C:2]2[C:3]([C:10]([CH3:11])=[N:14][NH:15]2)=[CH:4][CH:5]=1
Reactant: NN
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(C)n[nH]c2c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 51.4 %

Procedure:
To a stirred solution of 2′-fluoro-4′-methoxyacetophenone (0.5 g, 3.0 mmol) in ethylene glycol (10 mL) was added dropwise hydrazine hydrate (0.1 g, 3.1 mmol). The mixture was stirred for 24 h and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic layer was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:1)] to give an orange oil. The oil was dissolved in ethylene glycol (10 mL) and heated at 165° C. for 24 h. The solution was cooled to room temperature and partitioned between dichloromethane (20 mL) and water (3×20 mL). The organic extract was dried (magnesium sulfate), concentrated in vacuo and purified by column chromatography [SiO2; ethyl acetate-heptane (1:5)] to give the product (0.25 g, 51%) as a colourless solid: IR νmax (Nujol/cm−1) 1624, 1519, 1458, 1295, 1208, 1170, 1024 and 821; NMR δH (400 MHz, CDCl3) 2.54 (3H, s), 3.86 (3H, s), 6.78-6.81 (2H, m) and 7.52 (1H, d, J 9 Hz).
Reaction SMILES: F[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C>[CH2:19]([S:26][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Reactant: SCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1SCc1ccccc1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
A solution of 3.00 g (10.5 mmol) of 5-fluoro-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole and 1.48 ml (12.6 mmol) of benzylmercaptan is initially introduced into 24 ml of acetonitrile at 0° C. 4.78 ml (34.3 mmol) of triethylamine are then added dropwise and the reaction mixture is stirred for two hours at between 0° C. and 10° C. Following concentration by evaporation in vacuo, the resulting oil is purified by chromatography on silica gel, giving 3.19 g of 5-(benzylsulphanyl)-1-methyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole (78%).
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH2:14][CH:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.BrBr.[CH3:25][NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(O)CCCCCC.C1C=CC=CC=1>[CH2:27]([N:26]([CH3:25])[CH:12]1[CH:11]([O:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH:13]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCNC
Reactant: C1=C(OCc2ccccc2)CC(OCc2ccccc2)C1
Agent: BrBr
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCCCCO
Product: CCCCCCCOC1C(OCc2ccccc2)CC(OCc2ccccc2)C1N(C)CCCCCCC

Procedure:
0.23 g of sodium are dissolved in 30 ml of 1-heptanol at 50° under nitrogen. Dropwise, with stirring, there is added 4.88 g of N-heptyl-N-methyl-2-bromo-4,5-bibenzyloxycyclopentane-1-amine (obtainable from 3,5-dibenzyloxy-2-cyclopentene by the addition of bromine and reaction with 1-equivalent of methyl heptylamine), dissolved in 30 ml of benzene. Stirring is carried on for 6 hours at 50°. After cooling, 100 ml of benzene is added thereto. This is washed with water. The organic phase is dried over MgSO4 and the solvent is distilled off. After chromatographic purification of the residue (silica gel/chloroform:acetone=9:1), N-heptyl-N-methyl-5-heptyloxy-2,4-dibenzyloxy-cyclopentane-1-amine is obtained.