Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:27][CH:28]([NH2:30])[CH3:29].C(N(CC)C(C)C)(C)C>ClCCl>[CH:28]([NH:30][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:20]([CH3:22])([CH3:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]([O:25][CH3:26])=[O:24])[CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3])([CH3:29])[CH3:27]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC(C)C)c1)=N2
Yield: 59.1 %

Procedure:
To a stirred solution of methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (393 mg, 1.0 mmol) in dichloromethane (4 mL) was added propan-2-amine (60 mg, 1.0 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol). The resultant mixture was stirred overnight. The mixture was purified on preparative Thin layer chromatography to afford 245 mg of methyl 2-(3-(N-isopropylsulfamoyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate, which was used directly.
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:30]3[CH:31]=[CH:32][C:27]([C:19]4[S:18][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:28][CH:29]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(-c2nc3ccccc3s2)cc1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc21
Yield: 79.5 %

Procedure:
A mixture of 5.8 g of 9-Acetyl-3-bromocarbazole and 5.7 g of (4-benzo[d]thiazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.03 g of tetrakis(triphenylphosphine)palladium, 4.2 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 6.7 g of 9-acetyl-3-[(4-benzo [d]thiazol-2-yl) phenyl]-9H-carbazole as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([CH3:15])[NH:10]2)(=[O:3])[CH3:2].C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[C:1]([NH:4][C:5]1[C:6]2=[C:11]3[N:10]([CH:9]([CH3:15])[CH2:8][CH2:7]2)[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:18])[C:12]3=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(=O)Nc1cccc2c1CCC(C)N2
Product: CCOC(=O)c1cn2c3c(c(NC(C)=O)ccc3c1=O)CCC2C
Temperature: 160 °C

Procedure:
A mixture of 19 g of 5-acetamido-1,2,3,4-tetrahydroquinaldine and 24.0 g of diethyl ethoxymethylenemalonate was heated at 160° C. for 2 hours. The product obtained was not purified. To the mixture was added 60 g of polyphosphoric acid, and the mixture was heated at 100° C. for one hour. To the mixture was added 400 ml of warm water. The mixture was basified and cooled. The solid residue was separated by decantation to provide ethyl 8-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylate. Next the solid was dissolved in 20 ml of methanol, and to this solution was added 80 ml of ten percent sodium hydroxide solution. The solution was heated on a steam bath for one hour, followed by the addition of 20 ml of concentrated ammonium hydroxide. The solution was acidified to pH 6 with acetic acid. A solid precipitate formed which was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide brown crystals of 8-amino-6,7-dihydro- 5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. The structure was confirmed by infrared and nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH:36]1[CH:37]=[CH:38][C:39]2[N:44](O)N=[N:42][C:40]=2[CH:41]=1.O>CN(C=O)C>[NH2:42][C:40]1[CH:41]=[CH:36][CH:37]=[CH:38][C:39]=1[NH:44][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH2:5][NH:4][CH:1]2[CH2:2][CH2:3]2)=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C=C(CNC2CC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
To a solution of 4-(3-(cyclopropylamino)-2-(4-fluorophenyl)prop-1-en-1-yl)benzoic acid (0.4 g, 1.3 mmol) in DMF (5 mL), EDCl (0.49 g, 2.6 mmol), HOBt (0.175 g. 1.3 mmol) and TEA (0.54 mL, 3.9 mmol), were added, followed by n-phenylenediamine (0.280 g, 2.6 mmol). The reaction mixture was stirred at room temperature for 2 hours, subsequently the residue was poured into water and extracted with ethyl acetate (300 mL) and washed with water (3×50 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to afford the crude compound. The obtained compound was purified with flash chromatography using 15% ethyl acetate/hexane as the eluent, pure fraction evaporated to afford title compound (0.040 g, 9% yield). 1H NMR (DMSO-d6) δ (ppm): 0.24-0.25 (2H, m, —CH2), 0.37-0.39 (2H, m, —CH2), 2.13-2.14 (1H, m, —CH), 3.57 (2H, s, —CH2), 4.86 (2H, s, —NH2), 6.55-6.59 (1H, t, Ar—H), 6.70 (1H, s, ═CH), 6.74-6.76 (1H, d, Ar—H), 6.93-6.95 (1H, t, Ar—H), 7.02-7.04 (2H, m, Ar—H), 7.10-7.12 (1H, d, Ar—H), 7.16-7.26 (4H, m, Ar—H), 7.74-7.76 (2H, d, Ar—H), 9.52 (1H, s, —NH), MS m/z: 402.2 (M++1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:20]=2)=[N:11][CH:10]=1
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
5-Benzyloxy-2-(4-hydroxyphenyl)pyrimidine (2 g, 0.0072 moles, Example 30) was dissolved in 15 ml of N,N-dimethylformamide in a 50 ml flask and 0.2 g of dry sodium hydride was added. After stirring the mixture for 15 minutes, 1.39 g (0.0072 moles) of octylbromide was added and the mixture was heated to 100° C. for 2 hours. Upon cooling to room temperature, 15 ml of water was added. The resulting solid was collected by filtration and the solid was then slurried in boiling methanol, cooled to room temperature, and again collected by filtration. The solid was hydrogenated on a Parr Hydrogenator with catalytic 10% palladium on carbon in tetrahydrofuran under 413.7 kPa hydrogen pressure for about 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator to yield 1.62 g (75% yield) of 5-hydroxy-2-(4-(octyloxy)phenyl)pyrimidine.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:28][O:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:39]=1[N:38]=[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH:36]=[CH:35]2>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:43]2[CH2:44][CH2:45][N:40]([C:37]3[CH:36]=[CH:35][C:34]4[C:39](=[C:30]([O:29][CH3:28])[CH:31]=[CH:32][CH:33]=4)[N:38]=3)[CH2:41][CH2:42]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: COc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: COc1cccc2ccc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)nc12

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-methoxy-2-piperazin-1-yl-quinoline.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([O:21]C)=[O:20])=[CH:17][N:18]=3)[CH:15]=2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:15]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cnc2ccc(CCN3CCN(C)CC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(CCc2ccc3ncc(C(=O)O)n3c2)CC1
Temperature: 60 °C

Procedure:
To a stirring solution of methyl 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylate (113) (215 mg, 0.68 mmol) in THF:MeOH (4:1, 4 mL) was added 2N LiOH (3 mL). The reaction was heated at 60° C. for 45 minutes. The pH was adjusted between 4-5 with 1N HCl and concentrated. The crude product was purified by preparative HPLC to afford 6-(2-(4-methylpiperazin-1-yl)ethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (114). 1H NMR (400 MHz, d6-DMSO) δ 9.25 (s, 1H), 8.35 (s, 1H), 7.83 (d, J=9.2 Hz, 1H), 7.61 (dd, J=1.6, 9.2 Hz, 1H), 4.65-4.19 (m, 8H), 3.49-3.30 (m, 2H), 3.04-2.99 (m, 2H), 2.81 (s, 3H). MS m/z 316.1 (M+1)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[NH:29]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][CH3:41])(=[O:39])=[O:38])=[CH:33][CH:32]=1)[NH2:30]>>[N:13]1([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[C:21]3=[O:28])[CH:17]=[N:16][CH:15]=[N:14]1.[CH3:41][NH:40][S:37]([C:34]1[CH:35]=[CH:36][C:31]([NH:29][N:30]=[C:21]2[C:8]3[C:9](=[CH:10][CH:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[CH:7]=3)[NH:12][C:22]2=[O:27])=[CH:32][CH:33]=1)(=[O:39])=[O:38]
Reactant: Nc1ccc(-n2cncn2)cc1
Reactant: CNS(=O)(=O)c1ccc(NN)cc1
Agent: O=C1Nc2ccc(-n3cncn3)cc2C1=O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(-n4cncn4)cc32)cc1

Procedure:
5-[1,2,4]Triazol-1-yl-1H-indole-2,3-dione was prepared from 4-[1,2,4]-triazol-1-yl-phenylamine according to Procedure A in 6% yield: 1H NMR (DMSO-d6): δ7.04 (d, J=8.4Hz, 1H), 7.97 (d, J=2.2 Hz, 1H), 8.01 (dd, J=2.2, 8.4 Hz, 1H), 8.20 (s, 1H), 9.26 (s, 1H), 11.19 (bs, 1H); APCI−MS m/z 215 (M+1)+. Condensation of 5-[1,2,4]triazol-1-yl-1H-indole-2,3-dione with 4-hydrazino-N-methyl-phenylsulfonamide according to Procedure G gave the title compound in 86% yield: 1H NMR (DMSO-d6): δ2.38 (d, J=5.0 Hz, 3H), 7.05 (d, J=8.4 Hz, 1H), 7.30 (q, J=5.0 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.72 (d, J=8.7 Hz, 3H), 8.01 (s, 1H), 8.20 (s, 1H), 9.23 (s, 1H), 11.27 (s, 1H), 12.80 (s, 1H); Anal. Calcd for C16H15N7O3S.1.3H2O: C, 48.52, H, 4.22; N, 23.30; S, 7.62. Found C, 48.53, H, 4.25; N, 23.17; S, 7.55.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH2:15]1OCCOCCOCCOCCOCCOC1.CI.[H-].[Na+]>CN(C=O)C>[N+:11]([C:8]1[CH:7]=[CH:6][C:5]([CH:4]([CH3:15])[C:3]([O:2][CH3:1])=[O:14])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Yield: 697.9 %

Procedure:
A mixture of (4-nitro-phenyl)-acetic acid methyl ester (3.0 g, 15 mmol), 18-crown-6 (396 mg, 1.5 mmol), and methyl iodide (3.74 mL, 60 mmol) were combined in DMF (50 mL) and cooled to 0° C. Sodium hydride (660 mg, 16.5 mmol) was added. The solution was stirred with warming to room temperature overnight. The solution was partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 2.19 g (70%) of the title compound. MS (DCI) m/e 210 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].ClS([N:18]=[C:19]=[O:20])(=O)=O.O>C(Cl)Cl>[NH:1]([C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12])[C:19]([NH2:18])=[O:20]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NC(=O)c1c(N)sc2ccccc12
Solvent: O
Solvent: ClCCl
Product: NC(=O)Nc1sc2ccccc2c1C(N)=O
Yield: 40.9 %

Procedure:
To the mixture of 2a (20 mg, 0.104 mmol) in CH2Cl2 (10 mL) was added chlorosulfonyl isocyanate (15 μL, 0.15 mmol). The resultant mixture was stirred at room temperature for 1 h and mixed with water (0.5 mL). Separation via a reverse phase HPLC provided the title compound (10 mg, 40%) as a white solid: MS (ES) m/z 236 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ10.77 (s, 1H), 7.84 (m, 2H), 7.56 (brs, 3H), 7.20 (m, 1H), 7.08 (m, 1H), 6.98 (brs, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19](C3C=CC=C(C(F)(F)F)C=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-:46]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19]([Br:46])[CH:18]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: [Br-]
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as a white gum (0.976 g, 58%) from N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-hydroxy-benzamide using a procedure similar to Example 191. 1H NMR (DMSO-d6) δ 9.84 (s, 1H); 8.42 (t, 1H); 8.04 (d, 1H); 7.85–7.67 (m, 5H); 7.26–7.10 (m, 5H); 3.21 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.26 (m, 8H); IR (KBr) 3330, 2950, 2850, 1620, 1550, 1495, 1470, 1330, 1220, 1170, 1120, 1100, 1080 cm−1; mass spectrum [(+)APCI], m/z 549 (M+H)+; Anal. Calcd. for C28H29F3NO2: C, 61.32; H, 5.33; N, 2.55. Found: C, 61.02; H, 5.29; N, 2.51.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)([OH:6])=[O:5])[CH3:2].C(N(CC)CC)C.[C:43]([O:49][CH2:50]Cl)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:43]([O:49][CH2:50][CH:7]([P:4]([OH:6])([O:3][CH2:1][CH3:2])=[O:5])[C:8]1([C:13]([NH:15][C@H:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:17]2=[O:35])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]
Reactant: CCOP(=O)(O)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(O)C(COC(=O)C(C)(C)C)C1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1

Procedure:
0.6 g of tert-butyl (3S)-3-(1-ethylphosphono-methylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 17) were reacted with 1.73 ml of triethylamine, 0.86 ml of pivaloyloxymethyl chloride and 0.1 g of dimethylaminopyridine according to the method indicated in Example 6. After chromatography on silica gel (eluent: ethyl acetate), 392 mg of the title compound were obtained as a viscous resin, IR=1740, 1650 cm-1 (CH2Cl2); [α]D20 =-122.90° (c=0.257 in methanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[NH:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N.O1CCOC[CH2:19]1>>[CH:6]1[C:7]2[C:8]3[N:9]([CH:19]=[N:1][C:2]=2[N:3]=[CH:4][CH:5]=1)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:12]=3
Reactant: Nc1ncccc1-c1nc2ccccc2[nH]1
Reactant: C1COCCO1
Agent: N
Product: c1ccc2c(c1)nc1c3cccnc3ncn21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 100 mmol of the 2-(2-aminopyridin-3-yl)benzimidazole derivative (employed as equimolar mixture with the corresponding 2-tert-butylbenzimidazole derivative as obtained from synthesis 16)) and 1 mol of the corresponding carboxylic acid chloride is heated for 8 to 40 h under reflux in the case of carboxylic acid chlorides which boil below 150° C. or at 150° C. to 180° C. in the case of carboxylic acid chlorides which boil above 150° C., until the 2-(2-aminopyridin-3-yl)benzimidazole derivative has reacted. The reaction mixture is allowed to cool to 80° C., optionally diluted with 100 ml of dioxane, then stirred into a mixture of 500 ml of conc. ammonia solution and 500 g of ice and stirred for a further 3 h. The solid is subsequently filtered off with suction, washed twice with 100 ml of water in each case and dried in vacuo. The solid is taken up in 1000 ml of ethyl acetate, filtered through a short silica-gel column, rinsed with 500 ml of ethyl acetate, the ethylacetate is removed in vacuo, and the brown residue is recrystallised from methanol. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 170-200° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.CN(C=O)C.[H-].[Na+].[CH:18]([OH:21])([CH3:20])[CH3:19]>>[CH:18]([O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-chloro-5-nitro-pyridine (450 mg, 2.84 mmol) in isopropanol (10 mL)/DMF (7 mL) was added 60% NaH (57 mg). The mixture was stirred at 80° C. for 4 h and the organic solvents were evaporated under reduced pressure. The residue was partitioned between EtOAc and water. The EtOAc extracts were dried (Na2SO4) and evaporated. The crude product was used for the next step reaction without further purification. 1H NMR (300 MHz, CDCl3) δ 9.06 (d, J=2.81 Hz, 1H), 8.32 (dd, J=8.79 and 2.53 Hz, 1H), 6.74 (d, J=8.61 Hz, 1H), 5.43 (m, 1H), 1.38 (d, J=6.20 Hz, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Cl.Cl>CO>[F:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][S:13][CH2:12][C@@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[NH:10][C:8](=[O:9])[CH2:7][CH2:6][C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: Fc1ccccc1CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: N[C@@H](CCC(=O)N[C@@H](CSCc1ccccc1F)C(=O)NCC(=O)O)C(=O)O
Temperature: 50 °C

Procedure:
A mixture of 3.07 g of glutathione, 2.8 cc of triethylamine and 100 cc of methanol is brought to a boil. Then a solution of 1.45 g of o-fluorobenzyl chloride in 20 cc of methanol is added. After this addition, the resulting mixture is heated for 3 hours at 50°C, then allowed to cool and, by addition of dilute hydrochloric acid, 3.35 g of a white product are precipitated which can then be crystallized in water. Thus a product having a melting point of around 200°C (with decomposition) is obtained.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[C:13]([NH2:16])[N:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:23][CH:24]=O>CC(O)C>[Br:1][C:2]1[C:15]2[N:14]3[CH:23]=[CH:24][N:16]=[C:13]3[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCl
Reactant: Nc1nc2c(Br)cccc2c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Brc1cccc2c3ccccc3c3nccn3c12
Temperature: 75 °C
Yield: 62.6 %

Procedure:
To a mixture of 4-bromo-6-aminophenanthridine (19.11 g, 69.91 mmole), sodium bicarbonate (12.3 g, 146 mmole) in 2-propanol (200 ml) was added chloroacetaldehyde (50% aqueous soln. 17.35 g). After the reaction mixture was heated at 75° C. for 5 hrs., the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude mixture was purified by chromagraphy on silica gel using hexane/ethyl acetate (80/20) to obtain the title compound (13 g, 62%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][C:8]=1[F:29])=[O:5])[CH3:2].C(N(CC)CC)C.[C:37]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)(=[O:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:37]([N:40]1[CH2:45][CH2:44][CH:43]([N:20]2[CH2:21][C:16]3[C:15]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]4[CH3:28])=[N:14][C:13]([C:10]4[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:8]([F:29])[CH:9]=4)=[N:18][C:17]=3[CH2:19]2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNC3)cc1F
Reactant: CC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C2CCN(C(C)=O)CC2)C3)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.7 %

Procedure:
To (S)-1-ethyl-3-(2-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (intermediate 18) (100 mg, 0.23 mmol) and triethylamine (64 μL, 0.46 mmol) in dry THF (3 ml) was added 1-acetylpiperidin-4-one (56 μL, 0.46 mmol) and stirred at room temperature for 30 min. To this sodium triacetoxyborohydride (97 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature until analysis by LCMS indicated reaction was complete. The solvent was then removed in vacuo. Crude reaction mixture then was partitioned between ethyl acetate and water. The organic layer was recovered, dried with sodium sulphate and solvent removed in vacuo. Residue was then purified by prep HPLC (low pH) to afford a white solid (6.7 mg, 0.013 mmol, 6%).