Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]2[S:25][C:20]3=[N:21][CH:22]=[CH:23][N:24]=[C:19]3[CH:18]=2)=[O:16])[CH:13]=1)=[O:6].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH3:26][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:27]=[CH:28][N:29]=[C:2]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:3]=2)=[CH:13][C:12]=1[NH:14][C:15]([C:17]1[S:25][C:20]2=[N:21][CH:22]=[CH:23][N:24]=[C:19]2[CH:18]=1)=[O:16]
Reactant: Cc1ccc(NC(=O)c2ccnc(Br)c2)cc1NC(=O)c1cc2nccnc2s1
Reactant: C1CCNC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1NC(=O)c1cc2nccnc2s1
Temperature: 80 °C
Yield: 44 %

Procedure:
A mixture of N-(5-(2-bromoisonicotinamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 30 (25 mg, 0.053 mmol) in pyrrolidine (0.5 mL) was heated at 80° C. overnight. Quenched in 3% citric acid solution and extracted with CH2Cl2 (2×). The combined organic layers were dried with Na2SO4 and concentrated in vacuo. Purification by chromatography CH2Cl2/MeOH (97/3) and triturating with acetonitrile gave the title compound N-(2-methyl-5-(2-(pyrrolidin-1-yl)isonicotinamido)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 31b (10.7 mg, 44%). NMR (400 MHz, DMSO-d6) 1.97 (m, 4H), 2.26 (s, 3H), 3.45 (m, 4H), 6.88 (s, 1H), 6.98 (dd, J=5.1 and 1.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.23 and 1.6 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.1 Hz, 1H), 8.53 (br s, 1H), 8.75 (d, J=2.3 Hz, 1H), 8.88 (d, J=2.3 Hz, 1H), 10.33 (s, 1H), 10.52 (s, 1H). (m/z)=459 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:16])=[C:4]([C:9]([CH3:15])=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[NH4+].O>CO.[Fe]>[NH2:12][C:10]1[C:9]([CH3:15])=[C:4]([C:3]([F:16])=[C:2]([Br:1])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)c([N+](=O)[O-])cc(Br)c1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(C)c(N)cc(Br)c1F
Temperature: 70 °C
Yield: 102.3 %

Procedure:
To a solution of methyl 3-bromo-2-fluoro-6-methyl-5-nitrobenzoate (2.43 g, 8.32 mmol) in Methanol (80 ml) at room temperature was added ammonium chloride (4.37 g, 83.2 mmol) followed by deionized Water (40 ml). The mixture was heated to 70° C. in air before the addition of iron (2.79 g, 49.92 mmol). The reaction turned brown over the 2.5 hours it was stirred at 70° C. This mixture was allowed to cool to room temperature and was filtered through Kieselgel. The filter pad was washed with MeOH (80 ml) and the filtrate concentrated under reduced pressure. The residue was dissolved in saturated NaHCO3 (aq) (50 ml) and EtOAc (150 ml). The phases were separated and the organic phase was washed with saturated NaHCO3 (aq) (50 ml) before being dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (50 g silica, Isolute cartridge, gradient of eluents; 95:5 Heptane:EtOAc to 7:3 Heptane:EtOAc) to give 2.23 g (95%, 77% corrected yields) of methyl 3-amino-5-bromo-6-fluoro-2-methylbenzoate as a yellow oil. The material was taken through the next step without further purification. LC-MS 81%, 1.87 min (3 minute LC-MS method), m/z=261.9/263.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 6.89 (d, J=6.0 Hz, 1H), 3.94 (s, 3H), 3.60 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:14])(=[O:5])=[O:4].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]=[C:24]=[S:25]>CN(C)C=O>[Cl:12][C:11]1[CH:10]=[CH:9][C:8]([NH:13][C:24]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[S:25])=[C:7]([OH:14])[C:6]=1[S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: S=C=Nc1ccccc1Br
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccccc2Br)c1O
Yield: 71 %

Procedure:
A solution of N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (50 mg, 0.2 mmol) and 2-bromophenylisothiocyanate (43 mg, 0.2 mmol) in 0.5 mL of N,N-dimethylformamide was stirred at room temperature for 3 hours. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v) to give the desired product (66 mg, 74%). EI-MS (m/z) 465.5 (M+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>ClCCl>[C:1]1([CH2:7][CH2:8][NH:9][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85617.8 %

Procedure:
174.9 ml (1.39 mol) of phenylethylamine were dissolved in 600 ml of dichloromethane and admixed with 196.0 ml (1.41 mol, 1.01 eq.) of triethylamine. Subsequently, 221.0 g (1.39 mmol) of 3-fluorobenzoyl chloride were added dropwise to the solution at 0° C. such that the temperature did not rise above 40° C. The mixture was stirred at RT for 18 h and the precipitated solid was dissolved in 1000 ml of dichloromethane. The mixture was washed four times with 200 ml of dilute NaOH, 1N HCl and saturated NaHCO3 solution. The organic phase was removed, dried over MgSO4 and concentrated under reduced pressure. The solid was filtered off with suction and washed twice with a little dichloromethane. 289.52 g of a white solid were obtained with >99% purity (by HPLC), corresponding to 85.4% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=O.Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10]([C:12]([F:15])([F:14])[F:13])=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccc(Br)cc1N
Agent: Cl
Product: FC(F)(F)c1nc2cc(Br)ccc2[nH]1
Yield: 61.3 %

Procedure:
A mixture of 4-bromobenzene-1,2-diamine (3.0 g, 16.0 mmol), TFA (9.5 mL, 128.3 mmol) and aq. HCl (3 M, 32 mL) was heated to reflux overnight. The reaction mixture was concentrated and purified by column chromatography to afford the titled compound (2.60 g, 60%). LCMS: 265.0 [M+1]+. 1HNMR (400 MHz, DMSO-d6): δ 7.52 (dd, J=8.8 Hz, 1.2 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 14.20 (br, 1H).
Reaction SMILES: C(O)C.[SH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.Cl.Br[CH2:14][CH2:15][NH2:16].C(=O)([O-])[O-].[K+].[K+]>O>[NH2:16][CH2:15][CH2:14][S:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: Oc1ccc(S)cc1
Reactant: NCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: NCCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To 30 ml of ethanol, 1.2 g of 4-mercaptophenol, 2.1 g of 2-bromoethylamine hydrochloride and 1.4 g of potassium carbonate were added, followed by stirring for 3 hours at room temperature. Water was added, and the resulting mixture was extracted with ethyl ether. The extract was dried over MgSO4 and the ethyl ether was distilled off under reduced pressure, whereby 1.7 g of the compound (7) were obtained (yield: stoichiometric).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=2[F:29])[CH:3]=1.C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[F:29][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[CH2:19][C:4]1[CH:3]=[CH:2][N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])[CH:9]=[CH:10][C:5]=12)[NH2:26]
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc([N+](=O)[O-])cc3F)cc(Cl)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ccc2c(Cc3ccc(N)cc3F)ccnc21

Procedure:
270 mg (0.62 mmol) of 6-chloro-4-(2-fluoro-4-nitrobenzyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine are dissolved in 2 ml of ethanol. 170 μl (1.24 mmol) of triethylamine and 50 mg of 10% palladium-on-carbon are added. The mixture is hydrogenated at RT and a hydrogen pressure of 1.5 bar for 20 h. The mixture is filtered and concentrated, ethyl acetate is added and the mixture is washed with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulfate and concentrated. The product is reacted further without purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH2:12][NH2:13]>C(O)C>[CH2:6]([C:5]1[NH:13][N:12]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)[CH3:7]
Reactant: NN
Reactant: CCC(=O)CC(=O)C(F)(F)F
Solvent: CCO
Product: CCc1cc(C(F)(F)F)n[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1,1,1-Trifluoro-hexane-2,4-dione (1 g, 5.95 mmol) in absolute ethanol (10 mL) was added NH2NH2.xH2O drop-wise at 0° C. The reaction mixture warmed to the room temperature during 1 hour and refluxed overnight. Ethanol was then evaporated, residue dissolved in ethyl acetate (20 mL), washed consecutively with saturated brine solution and water, dried with Na2SO4 and concentrated to give the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([NH:24]C(=O)C(F)(F)F)[CH:3]=1.O1CCOCC1.[Cl-].[Na+]>N1CCCCC1>[NH2:24][C:4]1[CH:3]=[C:2]([CH3:1])[CH:23]=[CH:22][C:5]=1[C:6]([O:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][CH2:14]1)=[O:7]
Reactant: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(NC(=O)C(F)(F)F)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c(N)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.2 %

Procedure:
1.22 g (0.0029 mol) of 1-benzyl-piperidin-4-yl 4-methyl-2-trifluoroacetamido-benzoate were suspended in 60 ml of 1N aqueous piperidine in an ultrasound bath for 1/2 hr., treated with 10 ml of dioxan and subsequently stirred at room temperature for 20 hrs. Subsequently, the mixture was heated to 50° for 5 hrs. The suspension was treated with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated and the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2). 0.82 g (87%) of 1-benzyl-piperidin-4-yl 2-amino-4-methyl-benzoate was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:20][C:21]1[N:22](COCC[Si](C)(C)C)[CH:23]=[C:24]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:25]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:24]2[N:25]=[C:21]([CH3:20])[NH:22][CH:23]=2)[CH3:27])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: C#CC(C)(O)c1cn(COCC[Si](C)(C)C)c(C)n1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Product: Cc1nc(C(C)(O)C#Cc2cc3c(cc2F)OCCn2cc(C(N)=O)nc2-3)c[nH]1

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)but-3-yn-2-ol to give the titled compound after removal of the SEM protecting group (n-Bu4NF, THF). White solid (9 mg, 6%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH2:18])[C:12]([CH:19]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>S(=O)(=O)(O)O.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:18][C:30](=[O:32])[CH3:31])[C:12]([CH:19]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:20][CH2:21][CH:22]=[CH2:23])=[CH:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: C=CCCC(c1cc2cc(Oc3ccccc3)ccc2nc1NC(C)=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of the solid isolated in Step D (5.08 g, 17.6 mmol) in acetic anhydride (20 mL), sulfuric acid (1 drop) was added. The reaction mixture was stirred at room temperature for four hours. The reaction mixture was then concentrated to yield a residue. The residue was dissolved in ethyl acetate (300 mL). The resulting solution was extracted with sodium hydroxide (1.0 N) solution twice, hydrochloric acid (1.0 N) once, and brine once, and then was dried over magnesium sulfate. The solution was filtered and concentrated to yield N-{6-phenoxy-3-[1-(tetrahydro-pyran-4-yl)-pent-4-enyl]-quinolin-2-yl}-acetamide as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]2[CH:6]=[C:7]3[C:13]([CH3:15])([CH3:14])[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH2:16])=[CH:4][C:5]2[CH:6]=[C:7]3[C:13]([CH3:14])([CH3:15])[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: CC1(C)CCn2c1cc1cc([N+](=O)[O-])c(F)cc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1(C)CCn2c1cc1cc(N)c(F)cc12
Yield: 5 %

Procedure:
To a solution of 6-fluoro-1,1-dimethyl-7-nitro-2,3-dihydro-1H-pyrrolo[1,2-a]indole (600 mg, 24 mmol) in ethanol (15 mL) was added ammonium formate (600 mg, 9.5 mmol) and Pd/C (10%, 129 mg, 0.12 mmol). The mixture was refluxed for 10 min. The Pd catalyst was removed via filtration through Celite and washed with ethanol. The filtrate was concentrated and purified by column chromatography (20-40% ethyl acetate-hexanes) to provide 6-fluoro-1,1-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-amine (260 mg, 49%). ESI-MS m/z calc. 218.1, found 219.2 (M+1)+. Retention time 1.01 minutes.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([OH:20])=O)[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:25])([CH3:26])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C@@H:13]1[CH2:17][CH2:16][C@:15]([CH3:21])([C:18]([NH:32][CH2:31][CH2:29][OH:30])=[O:20])[C:14]1([CH3:23])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Reactant: NCCO
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@@H]1CC[C@](C)(C(=O)NCCO)C1(C)C

Procedure:
The product from Example 205 and ethanolamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.14 (s, 3H), 1.23 (s, 3H), 1.26-1.42 (m, 3H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.69-1.82 (m, 1H), 2.25-2.47 (m, 2H), 2.61-2.67 (m, 2H), 2.96-3.02 (m, 1H), 3.09-3.15 (m, 2H), 3.33-3.39 (m, 2H), 4.61 (t, J=5.3 HZ, 1H), 7.20 (t, J=5.5 Hz, 1H), 8.50 (s, 1H). (ESI+) m/z 438 (M+H)+. Anal. calcd. for C23H39N3O3S: C, 63.12; H, 8.98; N, 9.60. Found: C, 62.89; H, 8.84; N, 9.72.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7]>CO.[Pd]>[F:41][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH2:10][CH:9]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Yield: 98.4 %

Procedure:
A mixture of compound 16 (8.4 g) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated; yielding 7 g (100%) of (±)-1-[3,5-bis(trifluoromethyl) benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (compound 15).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH3:17].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: CCCCOc1ccc(O)cc1
Reactant: C=CCOc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=CCOc1ccc(C(=O)Oc2ccc(OCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
30.0 g of PPE, 5.00 g (28.1 mmol) of the compound (12) and 4.40 g (28.9 mmol) of p-butoxyphenol were dissolved in 100 ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 8.30 g of p-butoxyphenyl p-allyloxybenzoate (13) (yield: 94.6%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])#[N:4].Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br>CN(C)C=O>[C:3]([C:5]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)#[N:4]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1(C#N)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a stirred suspension of NaH (17.7 g, 0.443 mol) in N,N-dimethylformamide (200 mL) was added dropwise a solution of tert-butyl cyanoacetate (25.0 g, 0.177 mol) in N,N-dimethylformamide (100 mL) at 0° C. under N2. The mixture was allowed to warm up to ambient temperature, and stirred for 1 h. Then, bis(2-bromoethyl)ether (49.3 g, 0.177 mol) was added to the mixture, and the resulting mixture was stirred at 90° C. for 24 h. After cooling to 0° C., the mixture was washed with water (100 mL). The volatile components were removed by evaporation and the residue was precipitated with a mixture of ethyl acetate-toluene (1:2, 500 mL) and water (500 mL). The organic phase was washed with water (500 mL) three times, dried over Na2SO4, filtered and evaporated. The solid was washed with hexane, collected by filtration and dried in vacuo to give 19.0 g (57%) of the title compound as white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1>[C:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CN(C)c1ccncc1
Product: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Yield: 100 %

Procedure:
A stirred solution of ethyl 5-hydroxyindole-2-carboxylate (7.79 g) and 4-dimethylaminopyridine (20 mg) in acetic anhydride (80 ml) was heated at 80° C. for 4 hours. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate. Combined organic extracts were washed with hydrochloric acid (2 M), saturated aqueous sodium hydrogen carbonate solution, water, aqueous saturated sodium chloride solution and dried. The solution was concentrated in vacuo to yield the product as a yellow solid (9.39 g,100%). NMR: δ 1.20 (t, 3H), 2.10 (s, 3H), 4.19 (q, 2H), 6.86 (dd, 1H), 6.97 (d, 1H), 7.20 (s, 1H), 7.29 (d, 1H); m/z 248 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccnc1Oc1cccc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1Oc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
(3-(3-Methylpyridin-2-yloxy)phenyl)methanol from Step 1 (3.3 g, 15 mmol), in dichloromethane (50 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.34 mL, 18.4 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at RT for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the title compound (3.6 g, 99% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cccc2c(Cl)ccnc12
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc2c(Cl)ccnc12)c1ccccc1
Yield: 61.3 %

Procedure:
In a similar fashion using route 14 general procedure 26, 4-chloro-quinolin-8-ylamine 464 (228 mg, 1.28 mmol), benzenesulfonyl chloride (0.2 ml, 1.53 mmol) pyridine (0.21 ml, 2.56 mmol) in DCM (10 ml) gave the title compound (250 mg, 61%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].Cl.Cl.[CH:26]1([NH:29][CH:30]2[CH2:33][NH:32][CH2:31]2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][CH:30]2[CH2:33][N:32]([C:18]3[C:19]([F:21])=[CH:20][C:10]4[C:11]([CH:17]=3)=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=3[CH:9]=4)[CH2:31]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: C1CC1NC1CNC1
Agent: Cl
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CC(NC5CC5)C4)c(F)cc3cc2c1=O
Yield: 72.2 %

Procedure:
8-(3-Cyclopropylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 15, but starting with 1.45 g of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.7 g of 3-(cyclopropylamino)azetidine dihydrochloride. 1.35 g of 8-(3-cyclopropylamino-1-azetidinyl)3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 221° C. and then 245° C.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[N:16]1([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH-].[K+]>CN(C=O)C.O>[N:16]1([CH2:22][CH2:23][O:24][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: OCCN1CCOCC1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Temperature: 0 °C

Procedure:
To a solution of 2-nitro-4-trifluoromethyl benzonitrile (0.5 g, 2.3 mmol) and 2-morpholin-4-yl-ethanol (0.37 g, 0.34 ml, 2.8 mmol) in DMF (4 ml) was added dropwise a solution of KOH (0.23 g, 4.1 mmol) in water (1.5 ml). After 10 min the reaction was poured into ice water and the white crystalline product collected by filtration, washed with water and dried (0.5 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1ccc(-c2ccccc2)cc1
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(-c3ccccc3)cc2)n1C

Procedure:
The title compound, MS: m/e=345.4 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 4-ethynylbiphenyl.