Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].[CH:27](O)=[O:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH2:22][CH2:23][N:24]([CH:27]=[O:28])[CH2:25][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: O=CO
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCNCC3)cc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(C3=CCN(C=O)CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine (12.0 mg, 0.0307 mmol), formic acid (2.3 μL, 0.0615 mmol), TBTU (19.7 mg, 0.0615 mmol), DIPEA (26.8 μL, 0.154 mmol) and DCM (1 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.87 (d, J=7.3 Hz, 3 H), 2.36-2.58 (m, 2H), 3.63-3.80 (m, 2 H), 4.05-4.15 (m, 2 H), 5.26 (q, J=7.2 Hz, 1 H), 5.86-5.97 (m, 1 H), 7.18 (t, J=8.7 Hz, 1 H), 7.24-7.31 (m, 1 H), 7.32-7.54 (m, 2 H), 8.09-8.17 (m, 1 H), 8.22 (d, J=2.0 Hz, 1 H). MS (ES+): m/z 418.04 (100) [MH+]. HPLC: tR=3.40 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:20][CH2:19]1.C(N(CC)CC)C>CN1C(=O)CCC1.CO>[NH3:5].[Cl:8][C:7]1[C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)=[CH:3][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:5][CH:6]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(C)C(=O)Nc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)c(Cl)cn1
Product: N
Temperature: 210 °C
Yield: 150 %

Procedure:
A capped microwave reaction vial containing a solution of N-(4,5-dichloropyridin-2-yl)pivalamide (0.38 g, 1.54 mmol) (Synthesis 153-B), benzyl 4-(aminomethyl)piperidine-1-carboxylate (0.76 g, 2 eq) and triethylamine (0.43 mL, 2 eq) in NMP (3 mL) was heated at 210° C. for 1.75 hr under microwave irradiation, and then allowed to cooled. The reaction mixture was diluted with MeOH and adsorbed onto Isolute SCX-II acidic resin (10 g). The resin was washed with methanol, then 2M ammonia in methanol. The basic fractions were concentrated and the crude product was further purified by column chromatography, using a Biotage 40+silica column eluted with a gradient of EtOAc in hexane. The product contained residual NMP which was removed by a second ion exchange purification on Isolute SCX-II acidic resin, eluting with methanol, then 2M ammonia in methanol, to give benzyl 4-((5-chloro-2-pivalamidopyridin-4-ylamino)methyl)piperidine-1-carboxylate as a light yellow gum (0.53 g, 68%).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)[CH2:15][OH:16])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=C[CH:28]=1.[C:33]1(C)[C:34]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[CH2:15][O:16][S:39]([C:34]2[CH:33]=[CH:38][C:37]([CH3:28])=[CH:36][CH:35]=2)(=[O:40])=[O:41])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(CO)Oc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: c1ccncc1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)OCC(Oc2cnn(C(C)(C)C)c(=O)c2Cl)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 4 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-chloro-5-(2-hydroxy-1-(4-tert-butylphenyl)-1-ethyl)oxy-3(2H)-pyridazinone (0.25 g, 0.66 mmol) is added pyridine. Toluenesulfonyl chloride (0.15 g, 0.79 mmol) is then added to it and the mixture stirred for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with 5% copper sulfate solution and then with water and dried. After removing the solvent on the rotary evaporator the crude is purified by flash chromatography using ethyl acetate—hexanes as the eluting mixture.
Reaction SMILES: Cl[C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1.C(OCC)(=[O:23])C>O1CCCC1.O>[OH:23][C:2]1([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[S:3]1
Reactant: CN1C(=O)C(Cl)(c2ccc(O)cc2)Sc2ccccc21
Reactant: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C(O)(c2ccc(O)cc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
2-Chloro-3,4-dihydro-2-(4-hydroxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (0.1 g, compound No. 2) is dissolved in a mixture of tetrahydrofuran (2 ml) and water (1 ml), and the solution is standed overnight at room temperature. The mixture is poured into a mixture of ethyl acetate and water. The organic layer is dried over anhydrous sodium sulfate, and concentrated in vacuo to give 0.1 g (quant. yield) of the titled compound as amorphous powder.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH2:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>>[CH3:12][C:1]1[CH:2]=[C:3]([O:7][CH2:8][CH:9]([OH:11])[CH2:10][NH:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: Cc1cccc(OCC2CO2)c1
Product: COc1ccc(CCNCC(O)COc2cccc(C)c2)cc1OC

Procedure:
When 3-(m-tolyloxy)-1,2-epoxypropane (hereinafter referred to as TOEP) represented by the following formula (2): ##STR2## reacts with β-(3,4 -dimethoxyphenyl) ethylamine (hereinafter referred to as HVA) represented by the following formula (3): ##STR3## to give bevantolol of the above formula (1), the resultant bevantolol further reacts with TOEP of the starting material to produce a by-product represented by the following formula (4): ##STR4## Such consumption of the produced bevantolol causes its low yield.
Reaction SMILES: N1(S(C2C=CC([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=CC=2)(=O)=O)CCC1.Br[C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:45]=2[F:51])(=[O:42])=[O:41])=[CH:36][CH:35]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1>>[F:51][C:45]1[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=1[NH:43][S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:14]2[CH:15]=[C:16]3[N:22]=[C:21]([CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:31]4)[NH:20][C:17]3=[N:18][CH:19]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)c(F)c1
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)c(F)c1

Procedure:
The title compound is synthesized as described for 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) from 472 mg of 4-bromo-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide (compound C5) and 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/5-20 vol. % ethanol) yields 185 mg of the title compound as a waxy solid. ESI-MS: 522.2 (MH+). TLC: Rf=0.26 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br:31]C(F)(F)C(F)(F)Br>CCCCC.CCOCC>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:14]1[Br:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)n1cc(CCOC2CCCCO2)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)OC(=O)n1c(Br)c(CCOC2CCCCO2)c2ccccc21
Temperature: 25 °C

Procedure:
tert-Butyllithium (28.1 ml of a 1.7 mol solution in pentane) was added slowly to a stirred solution of 1-tert-butoxycarbonyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (15.0 g) in dry ether at −78° C. under a dry nitrogen atmosphere. During the addition the temperature was maintained below −65° C. The reaction was stirred at −78° C. for 45 min at which time 1,2-dibromotetrafluoroethane (6.24 ml) was added. The reaction mixture was then allowed to warm to room temperature over 18 h, after which time it was quenched with water (100 ml) and extracted into ether (250 ml). The organic layer was separated, washed with water (250 ml) and brine (250 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give an orange oil. Purification by flash chromatography (SiO2; n-hexane/ethyl acetate 10:1) afforded the product as a pale yellow oil (7.12 g); 1H (250 MHz, CDCl3) δ1.50-2.00 (6H, br m), 1.61 (9H, s), 3.05 (2H, t, J=7.5 Hz), 3.43 (1H, m), 3.56 (1H, m), 3.74 (1H, m), 3.91 (1H, m), 4.61 (1H, t, J=2.5 Hz), 7.26 (2H, m), 7.54 (1H, d, J=5.0 Hz) and 8.07 (1H, d, J=5.0 Hz).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:19]>>[CH2:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:3]3[C:8]([N:9]=[C:10]4[C:15]=2[CH:14]=[C:13]([O:16][CH3:17])[CH:12]=[CH:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21]1)[CH3:19]
Reactant: COc1ccc2nc3ccccc3c(Cl)c2c1
Reactant: CCN1CCC(N)CC1
Product: CCN1CCC(Nc2c3ccccc3nc3ccc(OC)cc23)CC1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 9-chloro-2-methoxyacridine and 1-ethylpiperidin-4-amine, the title compound was obtained; MS (Found M+1=336). 1H NMR (CD3OD, 400 Hz): 8.2.9-8.27 (d, 1H, J=8.8 Hz), 7.96-7.94 (d, 1H, J=8.8 Hz), 7.92-7.89 (d, 1H, J=9.6 Hz), 7.70-7.66 (m, 1H), 7.53 (m, 1H), 7.46-7.43 (m, 2H), 3.98 (s, 3H), 3.90-3.80 (m, 1H), 3.02-3.8 (bm, 2H), 2.46-2.41 (q, 2H, J=7.2 Hz), 2.05-2.00 (m, 4H), 1.93-1.83 (m, 2H), 1.11-1.08 (t, 3H, J=7.2 Hz).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]1[CH:58]=[C:59]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]=[C:60]2[CH2:66][CH2:67][NH:68][C:69]1[N:77]=[C:76]([C:78]2[C:79]3[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=3[S:81][CH:82]=2)[N:75]=[C:74]2[C:70]=1[N:71]=[CH:72][N:73]2[CH:87]([CH3:89])[CH3:88])=[O:55]>CN(C=O)C>[O:14]=[C:13]1[NH:12][C@H:11]2[CH2:10][S:9][C@@H:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:2]([NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:54]([O:56][C:57]3[CH:58]=[C:59]4[C:63](=[CH:64][CH:65]=3)[NH:62][CH:61]=[C:60]4[CH2:66][CH2:67][NH:68][C:69]3[N:77]=[C:76]([C:78]4[C:79]5[CH:86]=[CH:85][CH:84]=[CH:83][C:80]=5[S:81][CH:82]=4)[N:75]=[C:74]4[C:70]=3[N:71]=[CH:72][N:73]4[CH:87]([CH3:89])[CH3:88])=[O:55])=[O:3])[C@H:16]2[NH:15]1
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCN)cc34)nc(-c3csc4ccccc34)nc21
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)CCCC[C@@H]5SC[C@@H]6NC(=O)N[C@@H]65)cc34)nc(-c3csc4ccccc34)nc21
Reaction time: 0.17 h

Procedure:
To a solution of (+)-biotin (35 mg, 0.14 mmol) and Et3N (36 mg, 0.35 mmol) in DMF (1 ml) was added HATU (90 mg, 0.24 mmol). The mixture was stirred for 10 min, and then was added to a solution of (3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-yl 6-aminohexanoate (b) (68 mg, 0.12 mmol) in DMF (1 ml). The reaction mixture was stirred for 16 hr at rt and then was concentrated. The residue was purified by reverse-phase HPLC (C18 column, eluting with MeOH—H2O 0.05% TFA) to afford the title compound as an off-white solid. Example 210 showed an EC50 value in the % CD34+ assay of 2.1 μM.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19](O)=[O:20].[C:33](N1C=CN=C1)([N:35]1C=CN=[CH:36]1)=O.CNC.O>O1CCCC1.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[NH:12][CH:13]=[CH:14][CH:15]=3)[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[CH:17]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH3:32])[CH:23]=1)[CH2:18][C:19]([N:35]([CH3:36])[CH3:33])=[O:20]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(-c4ccc[nH]4)c3C2=O)ccc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(C(CC(=O)N(C)C)N2C(=O)c3cccc(-c4ccc[nH]4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
A mixture of 3-(1,3-dioxo-4-pyrrolylisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (1.29 g, 2.97 mmol), and carbonyldiimidazole (481 mg, 2.97 mmol) in tetrahydrofuran (13 mL) was stirred at room temperature for 2 h. To the mixture was added dimethylamine in tetrahydrofuran (1.7 mL, 2N, 3.4 mmol) and the mixture stirred for an additional 2 h. Water (70 mL) and methylene chloride (50 mL) was added to the mixture. The organic layer was separated, washed with brine (20 mL), and dried over magnesium sulfate. The solvent was removed in vacuo to give a brown solid. This solid was purified by column chromatography (silica gel, 1:5 ethyl acetate:methylene chloride+0.1% MeOH) to give 3-(1,3-dioxo-4-pyrrolylisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)-N,N-dimethylpropanamide as a yellow solid (750 mg, 55% yield): mp, 105-107° C.; 1H NMR (CDCl3) δ 1.43 (t, J=7 Hz, 3H, CH3), 2.88 (s, 3H, CH3), 3.00 (s, 3H, 2CH3), 3.04 (dd, J=4.9, 16 Hz, 1H, CHH), 3.82 (s, 3H, CH3), 3.91 (dd, J=10.2, 16.6 Hz, 1H, CHH), 4.09 (q, J=7 Hz, 2H, CH2), 5.82 (dd, J=4.9, 10.2 Hz, 1H, NCH), 6.35 (t, J=2 Hz, 2H, Ar), 6.77-6.81 (m, 1H, Ar), 7.11-7.15 (m, 4H, Ar), 7.52-7.56 (m, 1H, Ar), 7.63-7.71 (m, 2H, Ar); 13C NMR (CDCl3) δ 14.65, 34.71, 35.34, 37.02, 51.52, 55.83, 64.32, 110.48, 111.22, 112.76, 120.24, 120.66, 121.35, 122.02, 129.75, 132.00, 134.06, 134.94, 138.23, 148.15, 148.93, 166.19, 167.34, 169.58; Anal Calcd for C26H27N3O5+0.15H2O: C, 67.30; H, 5.99; N, 8.85. Found: C, 67.16; H, 5.88; N, 8.92.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([N:17]=[C:18]=[S:19])[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([NH:17][C:18]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN=C=S
Reactant: c1cnc(N2CCNCC2)cn1
Solvent: CCOCC
Product: CCCCNC(=S)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 80 ml. of anhydrous ether is added a solution of 3.45 g. of n-butyl isothiocyanate in 50 ml. of anhydrous ether, dropwise during 5 minutes. The mixture is stirred for 30 minutes and the resulting solid is collected and dissolved in 50 ml. of ethanol. Cooling and the addition of 2 ml. of water gives 4.96 g. of the desired product as white crystals, m.p. 97.5°-98.5° C.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: COC(OC)OC
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.77 mmol), trimethyl orthoformate (0.081 g, 0.766 mmol), p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated at reflux using Dean-Stark apparatus for 24 hours. Benzene was removed and toluene was added and an excess of trimethyl orthoformate (0.084 ml) was added to the reaction mixture. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated as a white crystal, mp 78–80° C.
Reaction SMILES: [CH3:1][Ge:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.Cl>C(O)(C)C.O1CCCC1.[OH-].[K+]>[CH3:13][Ge:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cccc([Ge](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[Ge](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Reaction time: 8 h
Yield: 23 %

Procedure:
3'-Trimethylgermylacetophenone (49 mg, 0.2 mmol) and methyl 4-formylbenzoate (37 mg, 0.23 mmol) was dissolved in 5 ml of a mixture of 50% isopropanol and tetrahydrofuran, 1 ml of 1N aqueous potassium hydroxide solution was added, and the mixture was stirred overnight. The reaction mixture was adjusted to pH1 with 2N hydrochloric acid and extracted with AcOEt. The extract was evaporated and the residue was purified by column chromatography on silica gel (eluent: MeOH-methylene chloride) and recrystallized from a mixture of AcOEt and n-hexane to give 17 mg of pale yellow prisms, m.p. 186°-188° C. (yield 22%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][N:14]([C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:36])[CH2:30][CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:24][CH:23]=1)=[O:20])[CH2:13]2.Br[C:38]1C=C2C(=CC=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH:31]1([CH2:30][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([NH:21][C:19]([N:14]3[CH2:13][C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:4]5[CH:3]=[N:2][N:1]([CH3:38])[CH:5]=5)[CH:11]=4)[CH2:15]3)=[O:20])=[CH:23][CH:24]=2)=[O:36])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Reactant: OB(O)c1cc[nH]n1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Product: Cn1cc(-c2ccc3c(c2)CN(C(=O)Nc2ccc(NC(=O)CC4CCCC4)cc2)C3)cn1

Procedure:
The title compound was prepared as described in Example 280, substituting 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1H-pyrazol-3-ylboronic acid and 5-bromo-N-(4-(2-cyclopentylacetamido)phenyl)isoindoline-2-carboxamide for 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.27 (s, 1H), 8.14 (s, 1H), 7.88-7.85 (m, 1H), 7.55-7.40 (m, 6H), 7.36-7.30 (m, 1H), 4.77-4.69 (m, 4H), 3.86 (s, 3H), 2.31-2.16 (m, 3H), 1.81-1.68 (m, 2H), 1.68-1.42 (m, 4H), 1.28-1.12 (m, 2H); MS (ESI(+)) m/e 444 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[C:23]([C:24]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=3)[CH2:9]2)=[O:25])[CH:27]=1)(=[O:17])=[O:18]
Reactant: FC(F)(F)c1ccc2c(c1)CCNC2
Reactant: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCOCC2)c(C(=O)N2CCc3cc(C(F)(F)F)ccc3C2)c1

Procedure:
Prepared in analogy to example 1.1 from 6-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline and 5-methanesulfonyl-2-morpholin-4-yl-benzoic acid (Example 2.4).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:28][C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 20 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, and the precipitate which appears is filtered out and rinsed with ethyl acetate. After the solution is concentrated under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered out. The solvent is eliminated under vacuum and the residue is precipitated from diethyl ether. The solid is recovered by filtration, rinsed abundantly with diethyl ether in order to produce a white powder with a yield of 65%. Melting point: 277-278° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:9]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[NH:30][C:31]([C@@H:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:38](=[O:48])[C@@H:39]([NH:43][C:44](=[O:47])[O:45][CH3:46])[CH:40]([CH3:42])[CH3:41])=O.C(O)(=O)C>CCOC(C)=O.C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[N:9]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:22][CH:21]=3)[CH:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:31]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38](=[O:48])[C@@H:39]([NH:43][C:44](=[O:47])[O:45][CH3:46])[CH:40]([CH3:42])[CH3:41])[NH:30][C:3]=4[CH:4]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1N)C(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2[nH]1)C(C)C
Temperature: 75 °C

Procedure:
The product from Example 191H (0.5 g, 0.696 mmole) was treated with acetic acid (5 mL, 87 mmole) and heated in an oil bath at 75° C. for 70 min. The reaction mixture was cooled to room temperature and concentrated in vacuo leaving an oily residue. The residue was dissolved in EtOAc (100 mL) washed with 10%0/NaHCO3 (20 mL) and 10% NaCl (20 mL), dried over anhydrous Na2SO4(s), filtered and solvent removed in vacuo leaving a brown foamy solid. The residue was dissolved in 10 mL CH2Cl2 and applied to a 12 g silica gel column. The column was eluted with a gradient of CH2Cl2/MeOH, 99/1 to 95/5 over 15 minutes and the product was isolated as a tan solid as a mixture of isomers (0.31 g). ESI(m/z)+: 702.3.