Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[F:6][C:7]1[N:8]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[C:10]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[N:11]=1>CN(C=O)C>[CH2:1]([S:3][CH2:14][CH2:13][CH2:12][C:10]1[N:11]=[C:7]([F:6])[N:8]([C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:9]=1)[CH3:2]
Reactant: CCS
Reactant: CS(=O)(=O)OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethanethiol in DMF was treated with sodium hydride, and then with 2-fluoro-4-(3-methanesulphonyloxypropyl)-1-triphenylmethylimidazole. After stirring at ambient temperature for 16 hours, the mixture was worked up by extraction and chromatography to give 4-(3-ethylthiopropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.2 (t, 3H); 1.85 (quintet, 2H); 2.48 (q, 6H); 6.24 (s, 1H); 7.0-7.4 (m, 15H). This thioether was dissolved in CH2Cl2, cooled to 0°, and treated in portions with one equivalent of 3-chloroperbenzoic acid, having the reaction closely by HPLC. Complete conversion to product occurred 10 minutes after the final addition of peracid. The solution was extracted with aqueous sodium bicarbonate, dried and evaporated to give 4-(3-ethanesulphinylpropyl)-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. in CDCl3 : 1.28 (t, 3H); 2.02 (quintet, 2H); 2.66 (m, 6H); 6.27 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:20][S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1)C.[OH-].[K+].Cl>O1CCCC1.CO>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[S:21]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4]([OH:29])=[O:3])[CH2:7][N:8]=1)=[CH:19]2)(=[O:23])=[O:22]
Reactant: CCOC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.7 %

Procedure:
Ethyl(2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.49 g) was dissolved in a mixed solvent of tetrahydrofuran (8 mL)-methanol (8 mL). Aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (0.25 g) in water (4 mL)) was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced, pressure. The obtained amorphous solid was crystallized from ethyl acetate-hexane to give the title compound (256 mg, yield: 56%) as pale-yellow crystals. MS:422(MH+). melting point >240° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][N:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:24](O)[CH2:25][CH2:26][CH2:27][CH2:28]C>O1CCCC1.[Ti]>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][N:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCO
Reactant: COC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Agent: [Ti]
Solvent: C1CCOC1
Product: CCCCCCOC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Yield: 21.4 %

Procedure:
5 g (0.016 mole) of 5-(3-methoxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone and 16.32 g (0.16 mole) of n-hexanol are extracted under reflux together with 3.64 g (0.016 mole) of titanium tetraethylate in 50 ml of absolute tetrahydrofuran for 12 hours over a Soxhlet extractor filled with 4 Å zeolite. The reaction mixture is concentrated to dryness, the residue is taken up in water and the mixture is extracted three times with methylene chloride; the combined organic phases are dried over sodium sulphate and concentrated in vacuo. The oil which remains is purified chromatographically over a silica gel column (eluant: cyclohexane/ethyl acetate 1:1) and the product is crystallized from ether. 1.3 g (21.4% of theory) of 5-(3-n-hexyloxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone of melting point 96°-97° C. are obtained.
Reaction SMILES: [N:1]1([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]C2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9]2)[CH2:6][CH2:5]1)(=[O:32])=[O:31]
Reactant: CCOC(=O)C1(N2CCNCC2)CCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(N2CCN(S(=O)(=O)c3ccccc3Cl)CC2)CC1
Yield: 63 %

Procedure:
Ethyl 1-(piperazin-1-yl)cyclobutanecarboxylate (0.20 mmol) was dissolved in CH2Cl2 (1 ml). Triethylamine (0.30 ml, 2.2 mmol), followed by 2-chlorobenzenesulfonyl chloride (64 mg, 0.30 mmol), was added at room temperature. The orange-colored solution was stirred at room temperature for 18 h before saturated NaHCO3 solution was added. The mixture was extracted twice with EtOAc. Combined organic layers were washed once with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 25% EtOAc/hexanes) to give ethyl 1-(4-(2-chlorophenylsulfonyl)piperazin-1-yl)cyclopropanecarboxylate (47 mg, 63% 2 steps) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.85 (m, 2 H), 1.23 (t, J=7.5 Hz, 3 H), 1.23 (m, 2 H), 2.98 (bs, 4 H), 3.14 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H), 7.37 (t, J=7.3 Hz, 1 H), 7.42-7.53 (m, 2 H), 8.00 (d, J=7.8 Hz, 1 H), 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.1, 45.7, 46.7, 48.8, 60.5, 126.9, 132.1, 132.2, 132.3, 133.6, 136.0, 173.8; ESI-MS: m/z 373.3 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][N:14]=1)=[O:12].[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][N:14]=2)=[O:12])=[O:29])[N:27]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1noc2ccccc12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2noc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isoxazole-3-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:6](=[O:16])[C:5]2([CH:19](C#N)[C:20]([O:22]C)=O)[C:17]#[N:18].C[OH:27]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:19][C:20](=[O:22])[NH:18][C:17]3=[O:27])[C:6](=[O:16])[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:8]2=[CH:9][CH:10]=1
Reactant: COC(=O)CN1C(=O)C(C#N)(C(C#N)C(=O)OC)c2cc(Cl)ccc21
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)C2(CC(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
A suspension of methyl [5-chloro-3-cyano-1-(2-methoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl](cyano)acetate, intermediate 46, (10.56 g, 29.19 mmol) in dry methanol (190 ml) was purged with hydrogen chloride at −78° C. for 45 minutes. The suspension was allowed to warm up to ambient temperature and further heated up to reflux for 4 hours. The solvent was removed in vacuo, the remaining solid was suspended in glacial acetic acid (300 ml) and heated up to reflux for 5 hours. Evaporation under reduced pressure gave a red-brown oil, which was redissolved in ethyl acetate (300 ml). The solution was washed with water (2×200 ml), the aqueous washes were once back-extrated with ethyl acetate (200 ml) and the organic extracts were dried (MgSO4) to give the title compound (10.87 g, quant.) as solidified foam (HPLC purity: 91%). MS (ESI+): 323.2; MS (ESI−): 321.1
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[CH:5][N:6]2[C:11]=1[C:10]([CH2:12][OH:13])=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>ClCCl>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[C:3]([CH2:1][CH3:2])=[C:11]3[N:6]([CH:5]=2)[CH:7]=[CH:8][CH:9]=[C:10]3[CH2:12][O:13][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)cn2cccc(CO[Si](C)(C)C(C)(C)C)c12
Reaction time: 48 h
Yield: 90.1 %

Procedure:
1-Ethyl-2-(4-benzyloxyphenyl)-8-hydroxymethylindolizine (21.3 g, 60 mmol), triethylamine (7.88 g, 78 mmol) and tert-butyldimethylsilylchloride (17.8 g, 118 mmol) was dissolved in 200 ml of dry dichloromethane, and the mixture was stirred for 2 days. The solvent was evaporated and the crude product was purified by column chromatography over silica gel 60, using diethyl ether as the eluent. Fractions containing the product were combined and the solvent was evaporated. The product was crystallised from diethyl ether and petroleum ether to afford 25.5 g (90%) of 2-(4-benzyloxyphenyl)-8-(tert-butyldimethylsilanyloxymethyl)-1-ethylindolizine as yellow crystals. M.p. 79-81° C. 1H--NMR (CDCl3, 200 MHz) δ: 0.01 (s, 6 H); 0.83 (s, 9 H); 1.02 (t, 3 H); 2.74 (q, 2 H); 4.92 (s, 2 H); 4.96 (s, 2 H); 6.25 (dd, 1 H); 6.61 (d, 1 H); 6.89 (d, 2 H); 7.11 (s, 1 H); 7.17-7.37 (m, 7 H); 7.59 (d, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][CH:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)(Cl)Cl>[CH3:21][O:20][C:19]1[C:6]2[C:5]3[CH:22]=[CH:23][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][C:4]=3[CH:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:8][C:7]=2[CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1-c1ccc(N)cc1C(c1ccccc1)O2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1cccc2c1-c1ccc(NS(C)(=O)=O)cc1C(c1ccccc1)O2
Yield: 79 %

Procedure:
The solution of Example 5F (200 mg. 0.66 mmole), pyridine (300 mg) and methanesulfonyl chloride (227 mg., 2.00 mmole) in chloroform (3 mL) was stirred for 1 hour, washed with aqueous HCl (1M), dried (Na2SO4), filtered and concentrated under reduced pressure. Toluene was added and then concentrated. Heptane was added and concentrated under reduces pressure to provide the titled compound (199 mg. 80%). 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 3H), 3.94 (s, 3H), 6.00 (s, 1H), 6.30 (s, 1H), 6.61 (d, J=2 Hz, 1H), 6.62 (dd, J=10 Hz, 2 Hz, 1H), 6.69 (dd, J=9 Hz, 1 Hz, 1H), 7.15 (t, J=9 Hz, 1H), 7.25 (dd, J=9 Hz, 2 Hz, 1H), 7.32-7.39 (m, 5H), 8.45 (d, J=9 Hz, 1H); MS (APCI) m/e 382 (M+H), 399 (M+NH4).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1)=[O:13].[C:24](Cl)(=[O:26])[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([S:20]([NH2:23])(=[O:21])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13])(=[O:26])[CH3:25]
Reactant: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12
Reactant: CC(=O)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-(3-amino-6-chloroindole-2-carbonyl)benzenesulfonamide (Example 142) and acetyl chloride. m.p.: 250-251° C. (ethanol/toluene)
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10]>CC#N>[Cl:5][CH2:6][CH2:7][NH:8][C:9]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:10]
Reactant: O=C=NCCCl
Reactant: CC(C)N
Solvent: CC#N
Product: CC(C)NC(=O)NCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
A solution of isopropylamine (3.00 g, 50.8 mmol) in MeCN (30 mL) was treated with 2-chloroethylisocyanate (6.00 g, 56.9 mmol), stirred at RT for 1 h and the resulting solid collected via filtration to afford 1-(2-chloroethyl)-3-isopropylurea (6.12 g, 73%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 5.96 (t, J=5.9 Hz, 1 H), 5.87 (d, J=7.7 Hz, 1 H), 3.62 (m, 1 H), 3.53 (t, J=6.3 Hz, 2 H), 3.25 (m, 2 H), 0.99 (d, J=6.5 Hz, 6 H); MS (ESI) m/z: 165.1 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][C:25]=1[F:34]>>[F:34][C:25]1[CH:26]=[C:27]([NH:30][C:31](=[O:33])[CH3:32])[CH:28]=[CH:29][C:24]=1[S:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[NH:15][C:2]1[C:3]2[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=2)[N:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)c(F)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3F)ccnc2n1
Yield: 54.3 %

Procedure:
The product from Example 2g (100 mg, 0.48 mmol) was reacted with the product from Example 39e (140 mg, 0.48 mmol) for 22 h at 120° C. following the procedure from Example 1g giving the title compound as a solid (120 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J=7.3 Hz, 3H), 1.86 (sextet, J=7.3 Hz, 2H), 2.06 (s, 3H), 2.36 (s, 3H), 3.01 (t, J=7.3 Hz, 2H), 6.28 (d, J=6.9 Hz, 1H), 7.12-7.35 (m, 5H), 7.55 (dd, J=12.1, 2.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 8.42 (d, J=6.9 Hz, 1H), 9.04 (d, J=8.8 Hz, 1H); MS (ESI+) m/z 461 (M+H)+, ESI− m/z 459 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[C:33]([CH3:41])[O:32][N:31]=1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[C:30]([CH3:29])=[N:31][O:32][C:33]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1COS(C)(=O)=O
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with methanesulfonic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester (prepared by mesylation of the commercially available 1,5-dimethyl-1H-pyrazol-3-yl)-methanol) gave the title compound. ES-MS m/e (%): 508.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH:12]=[O:13])=[CH:6][CH:5]=1)[CH3:2].[CH2:15]([Mg]Br)[CH3:16]>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:14])[CH:12]([OH:13])[CH2:15][CH3:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCOc1ccc(C=C(C)C=O)cc1
Solvent: CCOCC
Product: CCOc1ccc(C=C(C)C(O)CC)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-(4-ethoxyphenyl)-2-methylpropenaldehyde (10 g, 0.053 mol) in dried diethyl ether (150 ml) cooled to −15° C. and stirred under an atmosphere of nitrogen was added a solution of ethylmagnesium bromide in diethylether (3M, 19.3 ml) The reaction mixture was allowed to warm to room temperature and after ½ h poured onto ice cold aqueous hydrochloric acid (2M, 50 ml) and the organic phase washed with water and brine. The organic phase was dried over magnesium sulphate, filtered and evaporated to give 1-(4-ethoxyphenyl)-3-hydroxy-2-methylpent-1-ene as a colourless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.O>CN(C)C=O>[CH3:33][O:32][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:26]([O:28][CH2:29][CH2:30][CH3:31])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: C1COCCN1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCl)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCN3CCOCC3)c(OC)cc12
Temperature: 60 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
Propyl 3-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 322) (80 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (484 mg) and morpholine (0.15 ml) were added to the solution, and the mixture was stirred at 60° C. for 2 days. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (52 mg, yield 59%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([C:25]1C=C(C)C=C[C:26]=1S([O-])(=O)=O)[CH2:21][CH2:22]CC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH2:20][CH2:25][CH3:26])[CH3:22])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: CCCCCc1cc(C)ccc1S(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Benzyloxyindole (7) (8.81 g, 39.5 mmol, 1.0 equiv., supplied by Combi-Blocks) was dissolved in anhydrous DMF (100 mL) and the solution was cooled to 0° C. Dry sodium hydride (1.89 g, 78.9 mmol, 2.0 equiv.) was added slowly. The mixture was warmed to room temperature over 30 minutes. 2-Pentyl-tosylate was added dropwise. The mixture was stirred for 18 h. Water was added slowly (dropwise at first) to quench excess NaH. The resulting mixture was extracted once with ether, and then washed with water and brine, respectively. The organic phase was dried with MgSO4, and concentrated on a rotary evaporator to yield a crude oil. The crude product was purified by flash column chromatography (3:1 hexanes/ethyl acetate) to yield 5-(benzyloxy)-1-(pentan-2-yl)-1H-indole (8) as an amber oil (10.67 g) of approximately 90% purity, which was used in the next step without any further purification. 1H NMR (500 MHz, CDCl3) δ7.50 (d, J=7.3 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.17 (dd, J=8.9, 2.4 Hz, 1H), 6.96 (dd, J=8.9, 2.4 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 5.12 (s, 2H), 4.44 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.23 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([C:18](=[O:32])[C@@H:19]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:20]([CH3:22])[CH3:21])[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]([NH:23][C@@H:19]([CH:20]([CH3:22])[CH3:21])[C:18]([N:8]([CH2:7][C:6]([OH:33])=[O:5])[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)=[O:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 723 (240 mg, 0.53 mmol) in CH2Cl2 (4.0 mL) was added TFA (2.0 mL) and the reaction stirred at rt for 1 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene. The material was used directly in the next reaction without further purification. ##STR103##
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:19](O)=[O:20])=[CH:15][C:16]([F:18])=[CH:17][C:11]=2[N:10]=1.[CH3:23][C:24]1([CH3:38])[O:28][C@@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:26][O:25]1>>[F:22][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([C:19]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([O:30][CH2:29][C@H:27]4[CH2:26][O:25][C:24]([CH3:38])([CH3:23])[O:28]4)[CH:32]=3)=[O:20])[C:12]=2[N:13]=1
Reactant: CC1(C)OC[C@H](COc2cccc(N)c2)O1
Reactant: O=C(O)c1cc(F)cc2nc(-c3ccccc3C(F)F)[nH]c12
Product: CC1(C)OC[C@H](COc2cccc(NC(=O)c3cc(F)cc4[nH]c(-c5ccccc5C(F)F)nc34)c2)O1
Yield: 48 %

Procedure:
2-(2-(difluoromethyl)phenyl)-5-fluoro-1H-benzo[d]imidazole-7-carboxylic acid (145; 250 mg, 0.82 mmol) was coupled with (S)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline 146 (prepared as described for 133 in Example 33, steps 1-2, except using (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane in step 1) as outlined earlier. (S)-2-(2-(Difluoromethyl)phenyl)-N-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide 147 was obtained in 48% yield (200 mg). MS (ESI) calcd for C27H24F3N3O4: 511.17; found: 512 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[N:3]=1.COC1C=C2C(=CC=1)C=C(OCCO)C=C2.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:23][O:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=1)[CH:21]=[CH:20]2
Reactant: C1CNCCN1
Reactant: COc1ccc2cc(OCCOc3cncc(Cl)n3)ccc2c1
Agent: COc1ccc2cc(OCCO)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2cc(OCCOc3cncc(N4CCNCC4)n3)ccc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(6-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [0.94 g, 2.8 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(6-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.00 g, 11.6 mmol) and K2CO3 (0.50 g, 3.6 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.52 g (48%) which was obtained as a beige colored solid. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+ 380.1848, found 380.1845.