Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:10](SC)=[N:9]2)=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:16]([O:15][C:13]([N:11]1[C@H:12]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:10]1[NH:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: NCc1ccccc1
Reactant: CSC1=NC(c2ccc(F)cc2)CN1C(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2ccccc2)=N[C@@H](c2ccc(F)cc2)[C@H]1c1ccc(F)cc1
Temperature: 100 °C
Yield: 123.2 %

Procedure:
A mixture of intermediate 62 (0.5 g, 1.24 mmol), benzylamine (0.680 mL, 6.2 mmol) and MeOH (0.1 mL) is heated at 100° C. overnight. The reaction mixture is cooled to RT and purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 0.354 g of the product 160. 1H NMR (CDCl3) δ 7.55-7.25 (m, 6 H), 6.95-6.85 (m, 2 H), 6.80-6.60 (m, 6 H), 5.45-5.20 (m, 2 H), 4.75-4.55 (m, 2 H), 1.16 (s, 9 H)
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:15]=[O:16]>>[I:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[CH:15]=[O:16]
Reactant: CN(C)C=O
Reactant: Cn1nccc1I
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc(C=O)c1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a cooled (0° C.) solution of 5-iodo-1-methyl-1H-pyrazole (1.3 g, 6.3 mmol) in dimethyl formamide (2 mL), under an atmosphere of nitrogen, was added phosphorus oxychloride (1.72 mL, 18.8 mmol, 3.0 eq.). The resulting mixture was stirred at room temperature for 4 hr before partitioning between ethyl acetate (80 mL) and 2M aqueous potassium carbonate (80 mL). The aqueous layer was extracted again with ethyl acetate (80 mL). The organic extracts were combined and washed with water (3×50 mL) and then dried over magnesium sulphate. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as an orange solid (0.58 g, 39%).
Reaction SMILES: I[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH2:10]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:8][C:9]1([F:24])[CH2:14][CH2:13][C:12]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=2)=[CH:11][CH2:10]1
Reactant: CC1(C)OB(C2=CCC(F)(F)CC2)OC1(C)C
Reactant: Cn1nccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1C1=CCC(F)(F)CC1
Yield: 94.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using 5-iodo-1-methyl-1H-pyrazole (1.90 g, 9.14 mmol), 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.00 g, 4.10 mmol), tetrakis(triphenylphosphine)palladium (0) (240 mg, 0.208 mmol), cesium carbonate (2.70 g, 8.29 mmol), 1,4-dioxane (10 mL) and water (5 mL), to yield the title compound (767 mg, 94%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][N:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCBr
Reactant: c1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCN1CCC[C@@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
To a solution of Example 1 (0.2 g, 0.66 mmol) in DMF (5 mL) was added triethylamine (0.16 mL, 1.14 mmol) and methyl 3-bromopropionate (0.07 mL, 0.64 mmol). The resulting slurry was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (0.03 g, 13%); 1H NMR (400 MHz, CDCl3); δ 1.68-1.80 (m, 3H), 1.93-2.04 (m, 1H), 2.29 (q, J=8.4 Hz, 1H), 2.53 (t, J=7.2 Hz, 2H), 2.70 (m, 1H), 2.87 (m, 1H), 3.13 (m, 1H), 3.24 (m, 1H), 3.66 (s, 3H), 3.75 (m, 1H), 3.92 (s, 2H), 3.93 (m, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.16-7.20 (m, 3H), 7.27 (m, 2H); MS (m/z) 354.2 (M+1); LC (100.0%).
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:13]=[C:14]([C:18]3([CH2:22][NH:23]C(=O)OC(C)(C)C)[CH2:21][O:20][CH2:19]3)[CH:15]=[CH:16][CH:17]=2)[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:50][C:2]([F:1])([F:51])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:13]=[C:14]([C:18]3([CH2:22][NH2:23])[CH2:19][O:20][CH2:21]3)[CH:15]=[CH:16][CH:17]=2)[NH:5][N:4]=1
Reactant: CC(C)(C)OC(=O)NCC1(c2cccc(-c3ccnc4c3c(C(F)(F)F)nn4C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)COC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1(c2cccc(-c3ccnc4[nH]nc(C(F)(F)F)c34)c2)COC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
tert-Butyl N-[[3-[3-[3-(trifluoromethyl)-1-trityl-pyrazolo[3,4-b]pyridin-4-yl]phenyl]oxetan-3-yl]methyl]carbamate (58 mg, 0.08397 mmol) was dissolved in DCM (2 mL) and cooled to 0° C. Triethylsilane (39.06 mg, 53.65 μL, 0.3359 mmol) was added followed by TFA (0.5 mL). The reaction was stirred at 0° C. for 1 hour then the solvent removed under reduced pressure. The crude product was dissolved in DMSO and purified by FractionLynx. The fractions were passed through bicarbonate cartridges to obtain free base and lyophilised to give (3-(3-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)oxetan-3-yl)methanamine (7.8 mg, 25%).
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)(=O)C(C)(C)C.[OH-].[Na+]>C1COCC1.CO>[C:42]([O:41][C@@H:9]([C:10]1[C:32]([CH3:33])=[CH:31][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[CH2:8][OH:7])([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cncc(-c2cc(-c3nc4cc(C)c([C@@H](CO)OC(C)(C)C)c(-c5ccc(Cl)cc5)c4s3)ccn2)c1
Temperature: 40 °C

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(5′-methoxy-2,3′-bipyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)ethyl pivalate (40.5 mg, 0.063 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added NaOH (0.5 mL, 2N solution). The reaction mixture was heated at 40° C. for 4 h, cooled, diluted with satd. aqueous NH4Cl, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product which was used without further purification. LCMS-ESI+: calc'd for C31H31ClN3O3S: 560.2 (M+H+); Found: 560.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:6]=2[N:7]=1)[CH3:2].BrN1C(=O)CCC1=O>C1C=CC=CC=1>[CH2:1]([C:3]1[S:4][C:5]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=3[C:8](=[O:18])[C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2c(s1)CCc1cc(C)ccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CCc1nc2c(=O)c3ccc(C)cc3ccc2s1
Reaction time: 16 h

Procedure:
A solution of the product from step (i) (3.14 g) and N-bromosuccinimide (2.18 g) in benzene (40 ml) was irradiated with a 500 Watt halogen lamp for 2 h. The reaction mixture was partitioned between dichloromethane and water. The organic phase was further washed with water, collected, dried (MgSO4) and solvent evaporated under reduced pressure. The residue was dissolved in dichloromethane (25 ml) and triethylamine (10 ml) added. After stirring for 16 h the solvent/reagent were evaporated under reduced pressure. Purification was by chromatography eluting with 30-40% ethyl acetate in isohexane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]([CH3:19])[CH3:18])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1)[CH3:2].[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1.CCOC(C)=O.Cl>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:31](=[O:33])[CH3:32])[CH:9]=1)[C:15](=[O:29])[C@@H:16]([NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CN(Cc1cccc(N)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CN(Cc1cccc(NC(C)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 735 (435.0 mg, 1.06 mmol) in pyridine (3.0 ml) was added acetic anhydride (50 μL, 1.59 mmol) and the reaction allowed to stir overnight. The reaction was diluted with EtOAc and 1N HCl. The layers were separated and the organic phase washed with brine, dried over MgSO4, filtered and concentrated to dryness to provide 480 mg of 742. ##STR121##
Reaction SMILES: B(F)(F)[F:2].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([Br:16])[CH:12]=[CH:11]2.C(ON=O)(C)(C)C>C1COCC1.C(COC)OC>[Br:16][C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[C:6]([F:2])[CH:7]=[CH:8][CH:9]=2)[CH:14]=1
Reactant: Nc1cccc2ccc(Br)cc12
Reactant: FB(F)F
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: COCCOC
Product: Fc1cccc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of BF3-etherate (0.86 ml, 1.25 M in THF, 6.5 mmol) in 12 ml dimethoxyethane was added at −5° C. a solution of 8-amino-2-bromo-naphthalene (1.20 g, 5.4 mmol) in dimethoxyethane (12 ml) over a periode of 35 min. After 1 hour a solution of tert-butylnitrite (0.62 ml, 5.4 mmol) in dimethoxyethane (24 ml) was added and the mixture was stirred for two hours at r.t. and the solvent was removed under reduced pressure. Chlorbenzene (120 ml) was added and the reaction mixture was refluxed for 50 min and the mixture was concentrated. The solid was diluted in methylene chloride and washed with NaHCO3. The organic phase was dried over MgSO4, filtered and reduced to give the crude product. Chromatography on silica gel (hexane) afforded 721 mg (59%) of the product as a brown oil. MS: m/e=242 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]C(=O)C)=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1.[ClH:21]>C1COCC1>[Cl:21][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:15]1[N:16]([CH3:20])[N:17]=[CH:18][CH:19]=1
Reactant: Cl
Reactant: CC(=O)Nc1ccc(OCCBr)c(-c2ccnn2C)c1
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(N)ccc1OCCCl
Temperature: 150 °C

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (450 mg, 1.33 mmol), concentrated HCl (0.9 mL) in THF (4 mL) was heated with microwave irradiation at 150° C. for 30 minutes. The crude was concentrated in vacuo to give the title compound as a brown oil. Exact mass calculated for C12H14ClN2O 251.1. found 252.0 (MH+). This was used without purification in next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1.C(N(CC)CC)C.[F:27][C:28]([C:63]([F:66])([F:65])[F:64])([O:32][C:33]([F:62])([F:61])[C:34]([F:60])([C:56]([F:59])([F:58])[F:57])[O:35][C:36]([F:55])([F:54])[C:37]([F:53])([C:49]([F:52])([F:51])[F:50])[O:38][C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:29](F)=[O:30]>>[F:27][C:28]([C:63]([F:64])([F:65])[F:66])([O:32][C:33]([F:61])([F:62])[C:34]([F:60])([C:56]([F:57])([F:58])[F:59])[O:35][C:36]([F:54])([F:55])[C:37]([F:53])([C:49]([F:50])([F:51])[F:52])[O:38][C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:29]([O:1][CH2:2][CH2:3][CH2:4][Si:5]1([CH3:19])[O:12][Si:11]([CH3:14])([CH3:13])[O:10][Si:9]([CH3:16])([CH3:15])[O:8][Si:7]([CH3:18])([CH3:17])[O:6]1)=[O:30]
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCO)O[Si](C)(C)O1
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: C[Si]1(C)O[Si](C)(C)O[Si](C)(CCCOC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)O[Si](C)(C)O1
Yield: 65.3 %

Procedure:
A 50 mL round bottom flask equipped with a magnetic stirring bar and an addition funnel was charged with 7.7 g of 98% (3-hydroxypropyl)heptamethylcyclotetrasiloxane (22 mmoles) and 2.3 g of triethylamine (23 mmoles). The mixture was stirred and 15.0 g of 97% perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoyl fluoride (21.9 mmoles) was added dropwise. After complete addition of the acid fluoride a gas chromatographic analysis indicated that essentially all of the acid fluoride and most of the cyclosiloxane were consumed with predominately the formation of one product. A 25 mL portion of dilute hydrochloric acid was added to the flask and the two phase mixture was transferred into a separatory funnel and the aqueous layer separated from the siloxane layer. The siloxane layer was washed with two 25 mL portions of water and the siloxane layer was transferred into a 50 mL round bottom flask and distilled at 110° C. and 0.3 mm Hg to yield a fraction of 14.7 g (66% yield) of 97% [3-(perfluoro-2,5,8-trimethyl-3,6,9-trioxadodecanoyl)oxypropyl]heptamethylcyclotetrasiloxane (14.3 mmoles), which corresponds to formula (I) wherein m is 1, n is 3, X is OC(O), and RF is given by formula (II) wherein p is 3, or more specifically as shown in formula (VII) below wherein p is 3. The product was analyzed by spectroscopy with the following results: 1H NMR 400 MHz, CDCl3 : d 0.1 (s 21 H), 0.6 (t 2 H), 1.8 (p 2 H), 4.4 (m 2 H); 19F NMR 376 MHz, CDCl3 : d -81 (CF3), -82 (CF3), -83 (CF3), -85 (CF3), -130 (CF2), -132 (CF2), -144 (CF); IR (neat liquid on NaCl): cm-1 : 2970 (m), 1780 (s), 1245 (vs), 1200 (s), 1145 (s), 1070 (vs), 995 (s), 970 (s), 810 (vs), 750 (m). ##STR8##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]1([OH:32])[CH2:31][CH2:30][NH:29][CH2:28]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:29]3[CH2:30][CH2:31][C:27]([CH3:26])([OH:32])[CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC1(O)CCNC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C)(O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-methylpyrrolidin-3-ol. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, CD3OD) δ ppm 8.06-8.01 (m, 2 H), 7.84-7.82 (d, J=7.2 Hz, 1 H), 7.74-7.68 (m, 2 H), 7.57-7.53 (m, 2 H), 5.81 (s, 1 H), 5.26 (s, 2 H), 4.49 (s, 2 H), 4.12-3.31 (m, 3 H), 3.27-3.21 (m, 3 H), 2.44 (s, 3 H), 2.08 (s, 2 H), 1.50 (s, 3 H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])=[CH:3][CH:2]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([N:7]([CH3:20])[C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(-c2ccccc2)cc1)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
13.00 g (49.0 mmol) N-(Biphenyl-4-yl)-2,2,2-trifluoro-acetamide (II.1.a) is dissolved in 200 mL acetone and 13.5 g (98.0 mmol) potassium carbonate is added. 3.50 mL (55.7 mmol) methyl iodide is added and the mixture is stirred at RT over night. The solvent is evaporated. The residue is taken up in water and extracted with ethyl acetate. The organic phase is dried and the solvent is evaporated.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH2:21]1)[CH3:19]>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:17])[C:11]=2[N:10]=[C:9]1[C:22]1([OH:26])[CH2:23][CH2:24][CH2:25][N:20]([CH2:18][CH3:19])[CH2:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nccc2c1ncn2Cc1ccccc1
Reactant: CCN1CCCC(=O)C1
Product: CCN1CCCC(O)(c2nc3c(Cl)nccc3n2Cc2ccccc2)C1

Procedure:
Following the procedure of Example 13 and using 1-benzyl-4-chloro-1H-imidazo[4,5-c]pyridine (0.60 g, 2.5 mmol) and (0.36 g, 2.8 mmol) of N-ethyl-3-piperidone gave the free base of the title compound which was purified by flash chromatography on silica gel eluting with EtOAc to give, after preparation of the salt, the dihydrochloride, 0.59 hydrate as an amorphous solid, 0.30 g (26%):
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]([CH2:13]N(C)C)[CH3:12]>O1CCOCC1>[CH3:10][N:11]([CH2:13][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:12]
Reactant: N#Cc1cccc(O)c1
Reactant: CN(C)CN(C)C
Solvent: C1COCCO1
Product: CN(C)Cc1c(O)cccc1C#N

Procedure:
A mixture of 3-hydroxybenzonitrile (20.0 g) and N,N,N',N'-tetramethyldiaminomethane (22.9 ml) in 1,4-dioxane (200 ml) was heated on a steam bath for 48 hours. The mixture was evaporated to dryness and the residue dissolved in 2M hydrochloric acid. The solution was washed with ethyl acetate and then the acidic layer was basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give an oil which was purified by column chromatography on silica to give 2-dimethylaminomethyl-3-hydroxybenzonitrile. The structure was confirmed by 1H NMR spectroscopy.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.[CH2:16]([N:23]1[C:27]2=[C:28](Cl)[N:29]=[N:30][CH:31]=[C:26]2[CH:25]=[C:24]1[CH3:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN1CCCC1=O>[CH2:16]([N:23]1[C:27]2=[C:28]([O:13][CH2:12][C:11]3[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=3)[N:29]=[N:30][CH:31]=[C:26]2[CH:25]=[C:24]1[CH3:33])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc2cnnc(Cl)c2n1Cc1ccccc1
Reactant: OCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc2cnnc(OCc3ccc(F)cc3)c2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
32.65 g (291 mmol) of potassium tert-butoxide and 1.54 g (5.82 mmol) of [18]crown-6 (98% strength) are added successively to a solution of 21.8 g (173 mmol) of 4-fluorobenzyl alcohol in 150 ml of anhydrous N-methylpyrrolidone. This mixture is stirred at room temperature for 1 h. A solution of 15.0 g (58.2 mmol) of 1-benzyl-7-chloro-2-methylpyrrolo[2,3-d]pyridazine in 100 ml of anhydrous N-methylpyrrolidone is subsequently added dropwise in the course of 30 min. The mixture is stirred at room temperature for a further 15 min, then treated with 500 ml of ice-water and extracted with 3×400 ml of ethyl acetate. The organic extracts are washed with 3×300 ml of water and subsequently dried over magnesium sulfate. After concentration and crystallization from diisopropyl ether, 12.95 g (64%) of the title compound are isolated. M.p.: 127°-132° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:29]=[CH:30][CH:31]=1)[O:10][CH2:11][C:12]([NH:14][CH2:15][CH:16]([OH:28])[CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1)=[O:13]>CCN(CC)CC.C(Cl)Cl>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][N:18]1[CH2:17][CH:16]([OH:28])[CH2:15][NH:14][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:29]=[CH:30][CH:31]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Reaction time: 2 h

Procedure:
MsCl (23 mg, 0.2 mmol) was added to a cooled 0° C. stirred solution of 2-(3-aminophenoxy)-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)acetamide (71 mg, 0.2 mmol) in Et3N (0.1 mL) and DCM (10 mL). After stirred for 2 h, the solvent was removed by concentration. The residue was purified by prep-HPLC to afford the title compound. 1H NMR (400 MHz, MeOD): δ 7.26-7.22 (m, 1H), 7.11-7.01 (m, 4H), 6.91-6.85 (m, 2H), 6.71-6.68 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.69 (s, 2H), 3.43-3.88 (m, 1H), 3.13-3.12 (m, 1H), 2.96 (s, 3H), 2.89 (d, J=6 Hz, 1H), 2.82 (d, J=5.6 Hz, 1H), 2.57 (t, J=6 Hz, 1H) ppm; ESI-MS (m/z): 434.1 [M+1]+.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: C[n+]1ncc(N)cc1Cl
Reactant: SCc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[n+]1ncc(N)cc1SCc1ccccc1

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 200 parts of acetonitrile is stirred with 12.4 parts of benzylmercaptan and 20 parts of triethylamine for three hours at 80° C. The solvent is then distilled off at subatmospheric pressure, the residue is treated with about 300 parts of water and the sparingly soluble reaction product is suction filtered. 29.5 parts (89.2% of theory) of 1-methyl-4-amino-6-benzylmercaptopyridazinium perchlorate is obtained; C12H14O4N3SCl, melting point 139° to 141° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][CH2:2]/[CH:3]=[C:4]2\[CH2:5][CH2:6][CH2:7][C:8]3[C:13]\2=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[CH:20][CH:19]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1ccc2c(c1)C(=CCN)CCC2
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NC/C=C2\CCCc3ccc(OC)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 1-(2-aminoethylidene)-7-methoxy-1,2,3,4-tetrahydronaphthalene (3.0 g, 14.8 mmol) in THF (20 ml) was gradually added dropwise, under ice cooling, 4-methoxyphenyl isocyanate (2.2 g, 14.8 mmol). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was then poured into water. The organic layer was subjected to extraction with 10% methanol/chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (ethyl acetate:hexane=6:4), followed by recrystallization from ethyl acetate/methanol to give the above-titled compound (2.8 g, yield 54%).