Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[C:21](OCC)(=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9](=[O:11])[CH:10]=[C:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(O)=CC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
3-(2-Fluoro-biphenyl-4-yl)-butan2-one (Japanese Patent Unexamined Publication No. 54-144347) (116 mg) was dissolved in toluene (2 ml), followed by adding thereto sodium hydride (29 mg, 60% oily), and the mixture was stirred at room temperature for 1 hour. Then, diethyl oxalate (105 mg) was added and the resulting mixture was stirred at 40° C. for 3 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (163 mg).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH:29]([C:35]([O-])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>ClCCl>[CH2:1]([O:8][N:9]([C:35](=[O:36])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:10]1[N:20]=[CH:19][CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccnc1NOCc1ccccc1
Reactant: CCOC(=O)C(Cl)C(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ncccc1C(=O)OCC
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A solution of the product of Example 157A (1.2 g, 4.4 mmol) and triethylamine (0.49 g, 4.8 mmol) in dichloromethane (25 mL) was treated dropwise with ethyl chloromalonate (0.73 g, 4.8 mmol), stirred for 2 hr and partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to provide the title compound (1.1 g, 65%). MS (DCI) m/z 387 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:21]=1.[CH3:22][C:23]([OH:40])([CH3:39])[CH2:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[OH:40][C:23]([CH3:39])([CH3:22])[CH2:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[N:12]=[C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[S:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:21]=2)[CH:27]=[N:26]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(CO)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(NC(C)(C)CO)nc2-3)cn1
Yield: 18 %

Procedure:
2-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepine-2-ylamino)-2-methylpropan-1-ol from Example 356, was coupled with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol under Suzuki conditions to give 428. Yield 18%. MS (ESI+): 429.2. 1H NMR (400 MHz, DMSO) δ 8.14-8.04 (m, 2H), 7.87 (s, 1H), 7.29 (dd, J=8.2, 1.8, 1H), 7.17 (d, J=1.8, 1H), 7.07 (s, 1H), 4.97 (t, J=5.6, 1H), 4.70 (s, 1H), 4.26 (t, J=5.0, 2H), 4.02 (s, 2H), 3.58 (d, J=5.6, 2H), 3.05 (t, J=5.0, 2H), 1.34 (s, 6H), 1.09 (s, 6H)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH2:34])[CH3:31])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29](=[O:35])[N:30]([CH2:32][CH2:33][NH:34][C:18]1[N:17]=[C:16]([C:13]2[S:12][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[CH:14]=2)[C:21]([Cl:22])=[CH:20][N:19]=1)[CH3:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1)C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 74.3 %

Procedure:
A stirred mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (406 mg, 1.12 mmol), (2-aminoethyl)-methylcarbamic acid tert-butyl ester (486 mg, 2.79 mmol) and diisopropylethylamine (432 mg, 3.34 mmol) in 1,4-dioxane (4 mL) is heated at 95° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with EtOAc in dichloromethane 0-35%, to give {2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-methylcarbamic acid tert-butyl ester as a foam (418 mg, 75% yield). The intermediate is then subjected to deprotection by dissolving this material (415 mg, 0.827 mmol) in MeOH (12 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 2 hours, then concentrated to give the title compound as a yellow solid (352 mg, 90% yield). ES+(m/z) 402 (35Cl) and 404 (37Cl) [M(free base)+H].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)[N:3]=[CH:2]1.[CH3:25][NH2:26]>CO>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:24]=[CH:23][CH:22]=[CH:21][C:7]=2[O:8][CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:26][CH3:25])=[O:15])[N:3]=[CH:2]1
Reactant: CN
Reactant: COC(=O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Solvent: CO
Product: CNC(=O)c1ccccc1CCOc1ccccc1-c1c[nH]cn1
Temperature: 70 °C
Yield: 36.6 %

Procedure:
A mixture of methyl 2-(2-(2-(1H-imidazol-4-yl)phenoxy)ethyl)benzoate (30 mg, 0.093 mmol) and methylamine (2M, 3.3 mL, 6.51 mmol) in methanol was heated at 70° C. for 7 days. Methanol was removed under reduced pressure the crude product was purified by flash column chromatography to afford the desired product as a yellow solid (11 mg, 0.034 mmol, 37%). 1H NMR (CD3OD): 2.69 (s, 3H), 3.29 (t, 2H, J=6.4 Hz), 4.36 (t, 2H, J=6.4 Hz), 6.96 (dt, 1H, J=7.6 Hz, 1.2 Hz), 7.04 (d, 1H, J=8 Hz), 7.17-7.41 (m, 6H), 7.63 (s, 1H), 7.76 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17]([O:18]CC)=[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[N:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH2:26](Br)[CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15]1
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Reactant: OCCBr
Product: CCOC(=O)c1cn(CCO)c2nc(N3CCN(C)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-methyl-1-piperazinyl)-5-ethoxypyrido-[2,3-d]pyrimidine-6-carboxylate with ethylenebromohydrine, there is obtained the product, m.p. 197 - 199°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[C:10](=[O:20])[N:11]([CH2:13][C:14]3[S:18][C:17](Cl)=[N:16][CH:15]=3)[N:12]=2)=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:21][C@H:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[C:10](=[O:20])[N:11]([CH2:13][C:14]3[S:18][C:17]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[C:29]([F:40])([F:39])[F:28])=[N:16][CH:15]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=c1n(Cc2cnc(Cl)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1n(Cc2cnc(-c3ccccc3C(F)(F)F)s2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, 62 mg (0.14 mmol) of the compound from Example 31A and 40 mg (0.21 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 2 ml of toluene. 6.5 mg (0.007 mmol) of tris(dibenzylideneacetone)dipalladium, 5.6 mg (0.014 mmol) of 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl and 60 mg (0.28 mmol) of potassium phosphate were then added, and under argon the mixture was heated to 110° C. for 48 h. For work-up, the mixture was diluted at RT with 10 ml of ethyl acetate and 10 ml of water, the organic phase was separated off and the aqueous phase was extracted two more times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 10 mg (13% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH2:14][CH3:15])=[C:4]([CH2:16][O:17][CH3:18])[CH:3]=1.C([Li])CCC.[C:24](=[O:26])=[O:25].[ClH:27]>C1COCC1>[ClH:27].[CH2:14]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:24]([OH:26])=[O:25])=[CH:3][C:4]=1[CH2:16][O:17][CH3:18])[CH3:15]
Reactant: O=C=O
Reactant: CCC1CCCCN1c1ccc(Br)cc1COC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1CCCCN1c1ccc(C(=O)O)cc1COC
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-ethylpiperidine (1.42 g, 4.55 mmol) in anhydrous THF was added n-butyl lithium (2.4 mL, 6.82 mmol) in drops at −78° C. After 1 hour at −78° C., the reaction mixture was poured onto crushed dry-ice (100 g). Once the excess carbon dioxide was escaped, the reaction mixture was acidified with a 2N aqueous solution of HCl. The precipitate was filtered off and dried to afford the title compound as a solid (1.0 g, 70%). HPLC (Method A), Rt: 2.5 min (purity: 97.7%). LC/MS (Method A): 278.0 (M+H)+. 1H NMR (CD3OD, 400 MHz) δ 8.20 (1H, d), 8.07 (1H, s), 7.92 (1H, d), 5.05 (2H, m), 3.89 (1H, bs), 3.69 (4H, m), 2.39 (1H, d), 2.02-2.14 (2H, m), 1.72-1.95 (3H, m), 1.46 (2H, m), 0.88 (3H, t).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH2:20][CH3:21])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[C:27]1([CH2:33][CH2:34][CH2:35][NH2:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:20]([C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:36]([CH2:35][CH2:34][CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]2=[O:8])[CH3:21]
Reactant: CCOC(=O)C1C(CCl)C1(CC)c1cccc([N+](=O)[O-])c1
Reactant: NCCCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-ethyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 16, 3.5 g, 11.2 mmol), in N,N-dimethylformamide (33 ml) was added sodium hydrogen carbonate (3.3 g, 39 mmol) and 3-phenylpropylamine (10.6 g, 11.2 ml, 79.2 mmol). The mixture was heated to 150° C. for 12 h, then cooled to room temperature and partitioned between water (500 ml) and diethyl ether (500 ml). The organic layer was washed successively with water (4×250 ml). The aqueous layers were combined and extracted with diethyl ether (250 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (1.8 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl.CCCCCC>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug. Column chromatography of the plug with hexane: acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).
Reaction SMILES: C1(C([O:14][C:15](=[O:44])[CH2:16][O:17]/[N:18]=[C:19](/[C:38]2[N:39]=[C:40]([NH2:43])[S:41][CH:42]=2)\[C:20](=[O:37])[NH:21][CH:22]2[C:25]3([CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]([O:31][S:32]([OH:35])(=[O:34])=[O:33])[C:23]2=[O:36])C2C=CC=CC=2)C=CC=CC=1.[K].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.Cl>ClCCl.O.C1(C)C=CC=CC=1>[NH2:43][C:40]1[S:41][CH:42]=[C:38](/[C:19](=[N:18]/[O:17][CH2:16][C:15]([OH:44])=[O:14])/[C:20](=[O:37])[NH:21][CH:22]2[C:25]3([CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]([O:31][S:32]([OH:35])(=[O:33])=[O:34])[C:23]2=[O:36])[N:39]=1
Reactant: Nc1nc(/C(=N/OCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N(OS(=O)(=O)O)C23CCOCC3)cs1
Agent: Cl
Agent: [K]
Solvent: COc1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc(/C(=N/OCC(=O)O)C(=O)NC2C(=O)N(OS(=O)(=O)O)C23CCOCC3)cs1
Reaction time: 1 h

Procedure:
(Z)-[[[1-(2-Amino-4-thiazolyl)-2-oxo-2-[[2-oxo-1-(sulfooxy)-7-oxa-1-azaspiro[3.5]non-3-yl]-amino]ethylidene]amino]oxy]acetic acid diphenylmethyl ester, monopotassium salt (0.39 g, 0.57 mmole) was slurried in 6 ml of dry dichloromethane and 1.5 ml of anisole at -10° C. under argon and treated with 10 ml of trifluoroacetic acid. After 1 hour, dry toluene (12 ml) was added and the volatiles were removed in vacuo at 10° C. The residue was washed twice with hexane, then taken up in water and the pH adjusted to 6.75 with dilute potassium bicarbonate. Chromatography on HP-20 in water gave product mixed with inorganics. The impure product was lyophilized, taken up in water and the pH adjusted to 2.5 with dilute hydrogen chloride. Chromatography on HP-20 in a water-50% acetone:water gradient and lyophilization of the pure product fractions yielded the title compound as a white powder, 177 mg.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:41])([C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:5][CH2:6][CH2:7]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[F:3][C:4]([F:41])([C:19]([F:40])([F:39])[C:20]([F:38])([F:37])[C:21]([F:36])([F:35])[C:22]([F:34])([F:33])[C:23]([F:32])([F:31])[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:5][CH2:6][CH2:7][NH:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
3.95 g of methylamine is condensed in a solution of 4.3 g of 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluor-undecyltosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.1 g of (4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluor-undecyl)-methyl-amine is obtained as a crude product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: CN(C)CCN
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 56.5 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (145 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (202 mg, 0.56 mmol), and N,N-dimethylethylenediamine (276 μL, 2.4 mmol) are treated according to method E yielding 98 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-[2-(dimethylamino)ethylamino]quinoline. 38 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (16 μL) and triethylamine (120 μL).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1Br)(=[O:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)c1c(Br)[nH]c(-c2ccncc2)c1C
Product: CC(=O)c1c(-c2ccc(F)cc2)[nH]c(-c2ccncc2)c1C

Procedure:
The title compound was prepared from 3-acetyl-2-bromo-4-methyl-5-(4-pyridyl)-1H-pyrrole according to the procedure of Example 46 using 4-fluorophenylboronic acid instead of 4-pyridylboronic acid in step 3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH:11]=[CH:10][N:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:7])[CH:13]=1
Reactant: COc1ccccc1CCc1ccnc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1CCc1ccnc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {4-[2-(2-methoxy-phenyl)-ethyl]-pyridin-2-yl}-carbamic acid tert-butyl ester (143 mg, 0.435 mmol) in dry CH2Cl2 (3 mL) is treated with trifluoroacetic acid (1.0 mL, 13 mmol), and stirred at room temperature. After 18 hours, the reaction mixture is concentrated and the residue is dissolved in CH2Cl2 (10 mL), extracted with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to give the crude product which is used in the next reaction without purification.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(N(CC)CC)C.O[CH2:24][C:25]1([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C(OCC)C>[C:31]1(=[O:32])[C:25]2([CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH2:24][O:33]1
Reactant: O=C(O)C1(CO)CCOCC1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C1OCC12CCOCC2
Temperature: 0 °C
Reaction time: 20 h
Yield: 119.3 %

Procedure:
Trifluoromethanesulfonic anhydride (11.1 mL, 66.2 mmol), followed by triethylamine (17.8 mL, 127.4 mmol) was added to a slurry of 4-(hydroxymethyl)tetrahydropyran-4-carboxylic acid (10.20 g, 63.68 mmol) in anhydrous diethyl ether cooled to 0° C. (115 mL). The biphasic solution was stirred for 20 hours, warmed to room temperature, stirred an additional 2 hours. The layers were separated by decantation, and the lower layer diluted with 2% aqueous sodium bicarbonate solution (50 mL) and extracted with methylene chloride (4×200 mL). The combined organic extracts were washed with additional 2% aqueous sodium bicarbonate (100 mL), dried over magnesium sulfate, and concentrated in vacuo to afford 2,7-dioxaspiro[3.5]nonane-1-one as a pale yellow oil (10.8 g). IR (KBr) 1821 cm-1 ; 1HNMR (CD3Cl3) δ 1.92 (ddd, J=13.4, 8.1, 4.0 Hz, 2H) , 2.10 (dddd, J=13.4, 6.1,3.4, 0.8 Hz, 2H), 3.70 (ddd, J=11.8, 6.3, 3.9 Hz, 2H), 3.92 (ddd, J=11.8, 7.9, 3.4 Hz, 2H), 4.15 (s, 2H); 13CNMR (CD3Cl3) δ 30.78 (t), 55.78 (s), 64,46 (t), 71.50 (t), 173.42 (s), MS(EI) m/e=142. MS(CI) M+=H m/e=143, M++HNH4 m/e=160.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:16]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=2)=[CH:27][CH:28]=1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Product: Cc1nsc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)n1
Yield: 36.3 %

Procedure:
In analogy to example 29, 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine (65 mg, 0.33 mmol) was reacted with 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (98 mg, 0.33 mmol) to give the title compound (55 mg, 36%) as yellow foam.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:6]
Reactant: CCCC(N)CCC
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Product: CCCC(CCC)NC(=O)c1ccc(C)nc1Cl

Procedure:
Prepared in a similar manner to example 4 using 2-chloro-6-methylnicotinic acid and 4-Heptylamine. MS (M+H, 269).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[O:6][C:5]=1[NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])(=O)[CH3:2].[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>C(#N)C>[C:19]1([C@@H:16]([NH:15][C:5]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:14])[N:25]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:1]=2[CH3:2])=[O:6])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccnc1
Reactant: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(-c2cccnc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 170 °C
Yield: 29.9 %

Procedure:
A mixture of 4-acetyl-3-((S)-1-phenyl-propylamino)-isochromen-1-one (100 mg) and 3-aminopyridine (400 mg, excess) in acetonitrile (0.2 mL) was heated under microwave irradiation at 170° C. for 15 min. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (20 ml), and the organic phase was washed with water (3×10 ml). The product was extracted into aqueous phase with aq. 2M HCl (10 ml), the aqueous solution was neutralised with aq. 10% Na2CO3 and extracted again with ethyl acetate and evaporated. The obtained residue was purified by flash chromatography on SiO2 (5 g, gradient heptane-ethyl acetate, the product came out with 100% ethyl acetate) to give 37 mg of oil, which was precipitated from methanol (0.1 mL) and water (10 mL) with sonication for 10 min. The title compound was separated by filtration to give 10 mg of brown solid. LC-MS (m/z) 398.1 (MH+); tR=1.06. 1H NMR (250 MHz, 70° C., DMSO-d6): 0.93 (t, J=7.4 Hz, 3H, Me of Et), 1.72-1.88 (overlapping m, CH2 of Et), 1.85 (overlapping s, 3H, Me), 4.97 (q (dt), J=8 Hz, J=6.9 Hz, 1H, CHNH), 7.23 (m, 1H), 7.28-7.42 (m, 5H), 7.49 (t, J=7.6 Hz, 1H), 7.59 (dd, J=4.8 Hz, J=8.1 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.76 (d of dd, J=8.1 Hz, J=2.4 Hz, J=1.4 Hz, 1H), 8.21 (dd, J=8 Hz, J=0.8 Hz, 1H), 8.49 (d, J=2.4 Hz), 8.67 (dd, J=4.7 Hz, J=2.4 Hz, 1H), 8.72 (br d, J=8.2 Hz, NHCO).