Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)CCC>CS(C)=O>[CH2:12]([NH:19][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Solvent: CS(C)=O
Solvent: CCCCO
Product: Nc1nc(NCc2ccccc2)nc2[nH]cnc12
Temperature: 170 °C

Procedure:
2-chloroadenine (1) (2.81 g, 16.67 mmol) was divided among three microwave vials (10-20 mL), each containing Benzylamine (6 mL), 1-Butanol (8 mL,), and DMSO (1 mL). Each vial was heated to 170° C. for 90 minutes. After reaction completion the solvent was removed by rotary evaporation and triteration with diethylether gave 5.85 g of 71 as an off white solid pure enough for the next step. LCMS: m/z for C12H12N6++H observed 241.2 at 1.45 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:22])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:30](O)(=[O:32])[CH3:31]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:30](=[O:32])[CH3:31])[C:4]([NH:20][C@H:21]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH3:22])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:18])[CH3:19])[NH:13][N:12]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](C)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
(S)-3-(Aminomethyl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)-N6-(5-isopropoxy-1H-pyrazol-3-yl)pyridine-2,6-diamine (Example 18; 0.20 g, 0.49 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.49 mmol) were placed in a THF-DCM solution (1:1, 6 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.010 g, 49%). 1H NMR (400 MHz, CD3OD) δ 7.37-7.34 (m, 2H), 7.14 (d, J=10.9 Hz, 1H), 7.02-6.98 (m, 2H), 5.25 (s, 1H), 4.96-4.95 (m, 1H), 4.55-4.52 (m, 1H), 4.30 (d, J=14.8 Hz, 1H), 4.21 (d, J=14.8 Hz, 1H), 2.01 (s, 3H), 1.51 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 444. Found: [M+H]+ 445.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:54](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[N:17]([CH3:54])[N:18]=[N:19][N:20]=3)[CH2:15][C@@:9]1([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C@H:10]([O:21][C@H:22]([C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:44])([F:45])[F:43])[CH:33]=1)[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: FC(F)(F)c1cc([C@H](COCc2ccccc2)O[C@@H]2CC[C@H]3[C@H](c4nnn[nH]4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](COCc3ccccc3)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-2-phenylmethoxyethoxy}1-phenyl-6-(tetrazol-5-yl)-8-azabicyclo[3.2.1]octane (Example 158; 0.403 g, 0.57 mmol), methyl iodide (0.2427 g, 0.107 ml, 1.71 mmol) and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (10 ml) were heated at 60° C. for 2 hours. The mixture was quenched with water and concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organics were collected, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 1% methanol/dichloromethane to give the title compounds (isomer A; 60 mg) and (isomer B; 70 mg), together with mixed fractions.
Reaction SMILES: [H-].[Na+].[CH2:3]1COCC1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1.IC>O>[CH3:3][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][N:25]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26]3)[CH2:21][CH:22]=2)=[CH:9]1
Reactant: C1CCOC1
Reactant: O=c1c2ccccc2ncn1CCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1cc(C2=CCN(CCn3cnc4ccccc4c3=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A dried flask under nitrogen was loaded with sodium hydride (0.015 g, 0.37 mmol) and THF (10 mL). At 0° C. 3-[2-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)-quinazolinone (0.80 g, 2.16 mmol), was added and the mixture stirred for 15 minutes. Keeping the reaction temperature at 0° C., the iodomethane was added dropwise (0.14 mL, 2.16 mmol). This was allowed to warm to room temperature and stir overnight. Water was slowly added to the mixture to quench and the organics were extracted in chloroform, washed with water and dried over Na2SO4, filtered and concentrated. The residue was chromatographed using silica (2%_methanol:chloroform system); 0.52 g of 3-[2-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-4(3H)-quinazolinone was isolated as an orange solid. Yield 63%; MS: 384.9 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.79 (m, 2H), 3.17 (m, 4H), 3.20 (m, 2H), 3.61 (m, 2H), 3.76 (s, 3H), 4.44 (t, 2H), 6.12 (t, 1H), 7.00 (t, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.45 (m, 2H), 7.81 (m, 1H), 8.17 (d, 1H), 8.35 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7]([NH2:10])(=[O:9])=[O:8])=[C:5]([NH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([N:26]=[C:27]=[S:28])([CH3:25])[CH3:24]>CC(C)=O>[CH2:15]([O:14][C:12]([NH:11][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[S:7]([NH:10][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[S:28])(=[O:9])=[O:8])=[O:13])[CH3:16]
Reactant: CCOC(=O)Nc1cnn(C)c1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Nc1cnn(C)c1S(=O)(=O)NC(=S)NC(C)C
Temperature: 55 °C
Yield: 64 %

Procedure:
A mixture of 1-methyl-4-(ethoxycarbonylamino)pyrazole-5-sulfonamide (0.42 g), potassium carbonate (0.34 g) and isopropyl isothiocyanate (280 μl) in 10 ml of dry acetone was heated at 55° C. for 18 h and then evaporated to dryness. The residue was dissolved in 10 ml of water, and pH was adjusted to 2 by dropwise addition of 4M hydrochloric acid. The precipitate was filtered off, rinsed with a small amount of water and dried to give 0.38 g (64%) of the title compound; m.p. 141°-144° C.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[N:3]=[CH:2]1.CS[C:12](=[NH:14])[NH2:13].Cl>C(#N)C>[C:12]([N:6]1[CH2:7][CH2:8][C:9]2[NH:1][CH:2]=[N:3][C:4]=2[CH2:5]1)(=[NH:13])[NH2:14]
Reactant: c1nc2c([nH]1)CCNC2
Reactant: CSC(=N)N
Agent: Cl
Solvent: CC#N
Product: N=C(N)N1CCc2[nH]cnc2C1

Procedure:
A solution of 1.23 g of 4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine and 0.9 g of S-methyl-isothiourea in 15 ml of acetonitrile is refluxed for 8 h. After evaporation to dryness, the residue is treated with one equivalent of ethanolic hydrogen chloride. After cooling, 1.4 g of 5-guanyl-4,5,6,7-tetrahydro-imidazo-[4,5-c]-pyridine monohydrochloride, m.p. 310°, are collected.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24]CCCCCC>>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:24]
Reactant: CCCCCCCI
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Product: CCCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using 1-iodo-n-heptane as the alkylating reagent the title compound was obtained as a colorless oil (66% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1.OS(O)(=O)=O.[CH3:17]O>>[NH:1]1[C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:17])=[O:10])[S:8][C:4]=2[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2[nH]ncc2s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2[nH]ncc2s1

Procedure:
To a solution of 1H-thieno[3,2-c]pyrazole-5-carboxylic acid (G-1) (3.0 g, 17.9 mmol) in MeOH (50 mL) was added concentrated H2SO4 (0.3 mL). The reaction mixture was stirred at reflux for 60 h. Solvent was removed in vacuo. Ethyl acetate was added to dilute the mixture. The mixture was washed with aqueous NaHCO3 solution, dried over Na2SO4, and concentrated in vacuo to afford the title compound (2.4 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:46]=[C:45]2[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]2[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41][CH2:42][C:43](=[O:52])[N:44]3[CH2:47][CH2:48][CH2:49][O:50][CH3:51])=[CH:39][CH:38]=2)=[CH:13][CH:12]=1
Reactant: COc1ccccc1OCCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)CCc2ccc(CCl)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.200 g of tert-butyl 3-hydroxy-4-{4-[4-(2-methoxyphenoxy)butoxy]phenyl}piperidine-1-carboxylate and 0.125 g of 7-chloromethyl-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one (Example 13b) are reacted. The title compound is obtained as a colourless oil. Rf=0.12 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](N(OC)C)=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:6]([N:13]([CH3:22])[CH2:14][CH2:15][C:16](=[O:17])[CH2:1][CH2:2][CH2:3][CH3:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CON(C)C(=O)CCN(C)Cc1ccccc1
Reactant: [Li]CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(=O)CCN(C)Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Add butyllithium (12.3 ml (1.6 M solution in hexane), 19.6 mmol) to a stirred solution of 3-(benzyl-methyl-amino)-N-methoxy-N-methyl-propionamide and anhydrous tetrahydrofuran (70 ml) at −40° C. under N2. Stir for 1 hr at −40° C. Quench the reaction with saturated ammonium chloride (25 ml), allow the reaction to reach room temperature and add saturated sodium bicarbonate. Extract with ethyl acetate, wash with brine and dry over sodium sulfate. Filter off and concentrate to give the crude product. Purify the compound by flash chromatography, eluting with 2% ethanol/0.2% ammonium hydroxide/chloroform to yield 2.41 g (81%) of 1-(benzyl-methyl-amino)-heptan-3-one: mass spectrum (ion spray) m/z=234 (M+1); 1H NMR (CDCl3) δ 7.31-7.24 (m, 5H), 3.5 (s, 2H), 2.74-2.7 (m, 2H), 2.64-2.60 (m, 2H), 2.41 (t, 2H), 2.19 (s, 3H), 1.59-1.51 (m, 2H), 1.35-1.28 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[C:11]=1[C:12]([OH:14])=[O:13].C(N(CC)C(C)C)(C)C>C1COCC1>[F:9][C:10]1[CH:18]=[C:17]([O:19][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])[CH:16]=[C:15]([F:20])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1c(F)cc(O)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)c(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12 %

Procedure:
tert-Butyl(chloro)dimethylsilane (6.42 g, 42.6 mmol) was added to a solution of 2,6-difluoro-4-hydroxybenzoic acid (3.09 g, 17.8 mmol) in THF (50 mL), followed by the addition of N,N-diisopropylethylamine (9.19 mL, 51.5 mmol) over 5 min. After stirring at rt for 10 min the solution was concentrated in vacuo. Purification by gradient column chromatography, eluting with 10-50% solvent A in solvent B (A=DCM, B=DCM:MeOH:AcOH 95:5:1) yielded 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzoic acid (615 mg). This material was dissolved in THF (20 mL), borane-THF complex (1.0M in THF, 6.4 mL, 6.4 mmol) was added and the solution stirred at rt for 4 h. Further borane-THF complex (1.0M in THF, 6.4 mL, 6.4 mmol) was added and the solution stirred at rt for 18.5 h before concentration in vacuo. Purification by gradient column chromatography, eluting with 0-10% EtOAc in iso-hexane yielded 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzyl alcohol (470 mg). The title compound (533 mg, 0.90 mmol) was subsequently prepared from 2,6-difluoro-4-(tert-butyldimethylsilyloxy)benzyl alcohol (356 mg, 1.30 mmol) and (IntA1) (289 mg) using the methods of (77).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:3][C:4]([O:6]CC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24](=[N:26]O)[NH2:25]>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24]1[N:26]=[C:4]([CH2:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:1])[O:6][N:25]=1
Reactant: NC(=NO)c1cc(F)ccc1F
Reactant: CCOC(=O)CC(=O)c1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Cc1nc(-c2cc(F)ccc2F)no1

Procedure:
A solution of ethyl 3-oxo-3-o-tolylpropanoate (0.44 mL; 2.5 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 215 mg; 1.25 mmol) in toluene (1.5 mL) was heated to 120° C. 18 hours. The solvent was removed in vacuo and the residue purified by flash chromatography on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc. The residue was triturated with petrol to give the title compound as an off-white solid which was used directly without any further purification. 1H NMR (CDCl3, 400 MHz) δ 11.62‡ (1H, br s), 7.82-7.74 (1H, m), 7.55-7.12 (6H, m), 5.95‡ (1H, s), 4.68* (2H, s), [2.58, 2.55 and 2.47] (3H, s) (compound isolated as a mixture of keto and enol forms and as a mixture of rotamers, *=keto form, ‡=enol form). LC/MS: 315 (M+H)+. HPLC (Method D) Rt=4.28 min (Purity: 98.4%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][C:14]([Cl:27])=[CH:13][N:12]=2)[CH2:7][CH2:6]1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(#N)C>[Cl:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:16]1[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:6][CH2:7]2)=[N:12][CH:13]=[C:14]([Cl:27])[CH:15]=1)=[O:26]
Reactant: C1CCNCC1
Reactant: O=C(Nc1cc(Cl)cnc1N1CCC(CCCBr)CC1)c1cccc(Cl)c1
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cnc1N1CCC(CCCN2CCCCC2)CC1)c1cccc(Cl)c1
Temperature: 175 °C
Yield: 92.8 %

Procedure:
A mixture of 0.032 g (0.068 mmol) of N-[4-(3-bromo-propyl)-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl]-3-chloro-benzamide, 0.029 g (0.34 mmol) of piperdine, and 0.50 mL (2.8 mmol) in acetonitrile (1 mL) is heated at 175° C. in a microwave reactor for 30 minutes. The mixture is cooled to room temperature and purified by preparative reverse phase HPLC to give 0.030 g (93%) of the title compound (36) as a colorless foam. [M+H]+=475.3.
Reaction SMILES: [ClH:1].[CH2:2]([O:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7]1)[CH:3]=[CH2:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1>>[ClH:1].[CH2:2]([O:5][CH:6]1[CH2:11][CH2:10][C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)([OH:12])[CH:8]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:7]1)[CH:3]=[CH2:4]
Reactant: C=CCOC1CCC(=O)C(CN(C)C)C1
Reactant: COc1cccc(Br)c1
Agent: Cl
Product: C=CCOC1CCC(O)(c2cccc(OC)c2)C(CN(C)C)C1
Yield: 37 %

Procedure:
Base (13) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 1:4 ether/diisopropyl ether via a silica gel column and was taken up in 1:1 2-butanone/ether. After adding trimethylchlorosilane/water, compound (10) was obtained in a yield of 37% theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[N-:13]=[N+]=[N-].[Na+].O.C(=O)([O-])O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:13][CH2:7][CH2:6]2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)CCC2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCNC2=O
Yield: 43 %

Procedure:
To a solution of 5-methoxy-1-indanone (1.0 g) in TFA (20 ml) is added sodium azide (4.0 g), and the mixture is refluxed for 1.5 hour. After cooling, the reaction mixture is poured into water (100 ml), and the pH value of the mixture is adjusted to pH 7 with sodium hydrogen carbonate. The mixture is extracted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and dried over magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel; 100 g, chloroform/methanol=20:1). The fractions containing the title compound are concentrated under reduced pressure to give the title compound (470 mg) as a pale brown powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([CH:14]=1)[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:7][C:6]1[CH:14]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH2:15][Br:23])[CH3:13]
Reactant: CCOC(=O)COc1cc(F)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)COc1cc(F)ccc1CBr
Yield: 30.3 %

Procedure:
A solution of ethyl (5-fluoro-2-methylphenoxy)acetate (from Step 1) (0.65 g, 3.06 mmol), NBS (0.65 g, 3.68 mmol), and benzoyl peroxide (0.05 g, 0.21 mmol) in CCl4 (7.0 mL) were refluxed at 90° C. for 2.5 h. Additional NBS (0.16 g, 0.92 mmol) added, and reaction continued overnight. Solid filtered and filtrate concentrated onto silica gel. Purified by flash column chromatography using hexane and 2.5% EtOAc/hexane as eluent. Product obtained as yellow liquid (0.27 g, 30%). 1H NMR (CD3OD/400 MHz) δ7.37 (m, 1H), 6.69 (m, 2H), 4.80 (s, 2H), 4.60 (s, 2H), 4.23 (q, 2H, J=7.2 Hz), 1.27 (t, 3H, J=7.2 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[SH:20])/[C:17]([OH:19])=[O:18])=[CH:11][C:10]=1[O:21][CH3:22])C1C=CC=CC=1.II.O.S(=O)(O)[O-].[Na+]>O1CCCC1>[OH:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]2[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[S:20][C:13]=2[CH:14]=1
Reactant: COc1cc(/C=C(\S)C(=O)O)ccc1OCc1ccccc1
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cc(C(=O)O)sc2cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Z)-3-(4-Benzyloxy-3-methoxy-phenyl)-2-mercapto-acrylic acid (21 g) and iodine (21 g) in tetrahydrofuran (300 ml) was stirred in 60° C. for 15 hours. Then it was poured into water (1 l) and 120 g sodium bisulfite was added. The product was extracted into ethylacetate and then it extracted into sodium bicarbonate. The water phase was acified by concentrated hydrochloric acid and stirred in room temperature for one hour. The solid was filtered, washed with water and dried under vacuum.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([NH2:17])[CH:9]=[C:10]([F:16])[C:11]=2[CH3:15])[C:6]1=O)(=[O:3])[CH3:2].[CH2:19]([C@:21]1([OH:37])[C:33]2[CH:32]=[C:31]3[N:27]([CH2:28][CH2:29][C:30]3=O)[C:26](=[O:35])[C:25]=2[CH2:24][O:23][C:22]1=[O:36])[CH3:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([NH:4][CH:5]1[C:6]2=[C:29]3[CH2:28][N:27]4[C:31](=[CH:32][C:33]5[C@:21]([CH2:19][CH3:20])([OH:37])[C:22](=[O:36])[O:23][CH2:24][C:25]=5[C:26]4=[O:35])[C:30]3=[N:17][C:8]3[CH:9]=[C:10]([F:16])[C:11]([CH3:15])=[C:12]([C:7]=32)[CH2:13][CH2:14]1)(=[O:3])[CH3:2]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reactant: CC(=O)NC1CCc2c(C)c(F)cc(N)c2C1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)c(C)c3c1c2C(NC(C)=O)CC3
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To 150 mg of 2-acetylamino-8-amino-6-fluoro-5-methyl-1-tetralone and 158 mg of (4S)-4-ethyl-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione, 30 ml of toluene and then 150 mg of pyridinium p-toluenesulfonate were added, followed by heating at an external temperature of 120° C. under reflux for 28 hours. After completion of the reaction, the solvent was removed under reduced pressure. Acetone was added to the residue and crystals so precipitated were collected by filtration, whereby 169 mg of the title compound were obtained. Melting point: 225-235° C. (decomposed)
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[O:10]=[C:11]([C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:11]([C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)([OH:10])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:5]=1
Reactant: O=C(CCCCc1ccccc1)c1c[nH]cn1
Reactant: Fc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: OC(CCCCc1ccccc1)(c1ccc(F)cc1)c1c[nH]cn1
Temperature: 25 °C

Procedure:
0,52 g of magnesium turnings are covered with 60 ml of dry tetrahydrofuran. Then a solution of 1-bromo-4-fluorobenzene (3,8 g) in 60 ml of dry tetrahydrofuran is added dropwise to the mixture at such a rate that a smooth reaction is maintained. After the addition is complete, the reaction mixture is refluxed for one additional hour and cooled to room temperature. The reaction mixture is then added dropwise to a solution of 4-(1-oxo-5-phenylpentyl)-1H-imidazole (3,8 g) in 40 ml of tetrahydrofuran at 60° C. After the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and poured into cold water. Tetrahydrofuran is evaporated and conc. hydrochloric acid is added to the solution. The product is extracted as hydrochloric salt into methylene chloride. Combined methylene chloride extracts are then evaporated to dryness.