Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:9][N:8]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]1[CH3:18].[CH3:19][NH:20][CH3:21]>CO>[CH3:18][N:4]1[C:5]2[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[N:8]([CH:10]([CH3:12])[CH3:11])[CH2:9][CH:3]1[CH2:2][N:20]([CH3:21])[CH3:19]
Reactant: CC(C)N1CC(CCl)N(C)c2ccccc2C1=O
Reactant: CNC
Solvent: CO
Product: CC(C)N1CC(CN(C)C)N(C)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of 5.0 g (0.02 mole) of 2-chloromethyl-1,2,3,4-tetrahydro-1-methyl-4-(1-methylethyl)-5H-1,4-benzodiazepin-5-one, and 15.0 g (0.45 mole) of dimethylamine, and 200 ml of methanol were placed in a steel bomb and heated and stirred at 100° C. for 15 hr. After concentrating in vacuo, the residue partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue crystallized in isopropyl ether and was recrystallized twice from the same. It weighed 29.0 g (68%), m.p. 93°-95° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C:25]([N:8]2[CH2:9][CH:10]3[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]3)[CH2:7]2)=[O:26])=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: CC(C)N1CC2CNCC(C2)C1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)N1CC2CC(CN(C(=O)Cc3ccc([N+](=O)[O-])cc3)C2)C1
Reaction time: 3 h
Yield: 69.2 %

Procedure:
A standard setup was used with a N2 inlet. Initially, the amine 105 (2.42 g, 14.38 mmol) in H2CCl2 (35 ml) was added followed by NaOH (10%, 14.42 g, 35.95 mmol) which resulted in a heterogenous mixture. To this mixture was added 4-nitrophenylacetyl chloride (3,16 g, 15.82 mmol) dropwise over a 15-min period. Stirring was continued for an additional 3 h upon which the brown mixture was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted (H2CCl2, 3×25 ml), and the organic layers were combined. After drying (Na2SO4, 2 h), the organic solution was filtered and concentrated to give 94 as a light brown solid (3.3 g, 69.2 %); mp 93°-94° C. IR (KBr) 3090 (Ar-H), 2960, 2920, 2800, 2740 (C-H), 1625 (NC=O) cm-1 ; 1H NMR (DCCl3) d 0.94 (dd, 6 H, CH3 isopropyl), 1.69 [q, 2 H, H(9)], 1.92 ]bs, 2 H, H(1,5)], 2.46 [m, 3 H, ring protons, C-H isopropyl), 2.79 (d, 1 H, ring proton), 2.93 (td, 2 H, ring protons), 3.39 (d, 1 H, ring proton), 3.79(s, 2 H, CH2 -Ar), 3.84 (d, 1 H, ring proton), 4.57 (d, 1 H, ring proton), 7.44 (d, 2 H,-Ar-H), 8.15 (d, 2 H, Ar-H); 13C NMR (DCCl3) ppm 16.83, 18.44 (CH3 isopropyl), 28.76, 29.42 [C(1,5)], 31.57 [C(9)], 40.62 (CH2 -Ar), 46.76 (C-H isopropyl), 50.60, 52.78, 54.03, 54.42 [C(2,4,6,8)], 123.37, 130.02, 143.58, 146.56 (Ar-C), 167.93 (NC=O). Amide 94 was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[NH2:28][C:22]1[N:23]=[C:24]([NH:27][C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH:25]=[CH:26][C:21]=1[C:19]1[O:18][N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:20]=1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 2 h
Yield: 6.9 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridine-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and dichloromethane (1 mL) were added triethylamine (22 μL, 0.16 mmol) and methoxyacetyl chloride (15 mg, 0.14 mmol) at room temperature, which was stirred for 2 hours at the same temperature. The solids that precipitated in the reaction mixture were filtered out. Tetrahydrofuran was added to the solid thus obtained, and this mixture was filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.4 mg, 7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@@H:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-5-amino-2-(benzyloxycarbonylamino)pentanoic acid (50 g, 188 mmol) was dissolved in THF (800 mL) and water (100 mL). Tert-butyl 4-oxopiperidine-1-carboxylate (37 g, 188 mmol) was added and the reaction was stirred for 1 hour. The reaction was cooled to 0° C. and sodium cyanoborohydride (12 g, 188 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to provide (S)-2-(benzyloxycarbonylamino)-5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pentanoic acid, which was used directly in the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].FC(F)(F)[C:16](O)=[O:17]>C1N2CN3CN(C2)CN1C3>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:16]=[O:17])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCCCCCCc1ccc(C=O)cc1

Procedure:
88 g of n-heptylbenzene are taken up in 50 ml of trifluoroacetic acid and 70 g of hexamethylenetetramine. The whole is refluxed for 12 hours after which the excess of trifluoroacetic acid is distilled off by means of a water jet airpump. The mixture is then poured in ice water and neutralized with soda. After extraction with ether the resulting ether solution is evaporated and the resulting 4-heptylbenzaldehyde is used for the following process step.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:72]1([CH3:82])[CH:77]=[CH:76][C:75]([S:78](Cl)(=[O:80])=[O:79])=[CH:74][CH:73]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[S:78]([C:75]1[CH:76]=[CH:77][C:72]([CH3:82])=[CH:73][CH:74]=1)([O:65][CH2:64][CH:22]1[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]1)(=[O:80])=[O:79]
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 120 h
Yield: 96.1 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (68.5 g, 74.5 mmol) was dissolved in chloroform (700 ml), pyridine (26.9 ml, 0.33 mol), DMAP (903 mg, 7.39 mmol) and p-toluenesulfonyl chloride (44.9 g, 0.236 mol) were added, and the mixture was stirred for 5 days. The solvent was evaporated, and the residue was precipitated with acetonitrile (700 ml) and washed with acetonitrile (700 ml) to give 3,4,5-tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([N:49]4[CH2:54][CH2:53][NH:52][C:51](=[O:55])[CH2:50]4)=[CH:45][CH:44]=3)=[CH:39][CH:38]=2)[N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C:23](=[O:25])[N:22](COCC[Si](C)(C)C)[S:21]3(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH:13]=1.I[CH:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>>[CH:57]1([N:52]2[CH2:53][CH2:54][N:49]([C:46]3[CH:45]=[CH:44][C:43]([C:40]4[CH:41]=[CH:42][C:37]([CH2:36][C:11]5[N:12]([C:14]6[CH:15]=[CH:16][C:17]([N:20]7[CH2:24][C:23](=[O:25])[NH:22][S:21]7(=[O:35])=[O:34])=[CH:18][CH:19]=6)[CH:13]=[C:9]([C:3]6[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=6[Cl:1])[N:10]=5)=[CH:38][CH:39]=4)=[CH:48][CH:47]=3)[CH2:50][C:51]2=[O:55])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O
Reactant: IC1CCCCC1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCN(C6CCCCC6)C(=O)C5)cc4)cc3)cc2)S(=O)(=O)N1

Procedure:
4-[4′-(4-(2,4-Dichloro-phenyl)-1-{-4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one (17 mg, 0.02 mmol) was treated as described in general procedure L [using iodocyclohexane (13 mg, 0.06 mmol)] and general procedure W stepwise to give 1-cyclohexyl-4-(4′-{4-(2,4-dichloro-phenyl)-1-[4-(1,1,4-trioxo-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-imidazol-2-ylmethyl}-biphenyl-4-yl)-piperazin-2-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:59][CH3:60])[C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=[O:58])[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH:33]=2)=[C:8]([C:10]2[CH:11]=[C:12]([CH:27]=[CH:28][N:29]=2)[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:14])[CH:9]=1)[CH3:2].C(N(C(C)C)CC)(C)C.C1C([N+]([O-])=O)=CC=C([Cl-][C:80]([O-])=[O:81])C=1.[O:83]1[CH2:88][CH2:87][N:86]([CH2:89][CH2:90][NH2:91])[CH2:85][CH2:84]1>C(Cl)Cl>[O:83]1[CH2:88][CH2:87][N:86]([CH2:89][CH2:90][NH:91][C:80](=[O:81])[O:57][CH2:56][CH2:55][O:54][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([C:31](=[O:58])[NH:30][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:59][CH3:60])=[CH:9][C:8]=3[C:10]3[CH:11]=[C:12]([C:13](=[O:14])[NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:27]=[CH:28][N:29]=3)[CH:33]=2)[CH2:85][CH2:84]1
Reactant: NCCN1CCOCC1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCO)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(COCCOCCOCCOCCOCCOCCOC(=O)NCCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a mixture of Example 168 (50 mg, 0.060 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in DCM (1 mL) was added 4-nitrophenylchloroformate (52 mg, 0.26 mmol) and the solution stirred for 1 h. 2-Morpholinoethanamine (46 μL, 0.36 mmol) was then added and the solution stirred for 1 h, then the solvent removed and the residue purified by reverse-phase HPLC eluting with a water/acetonitrile gradient containing 0.1% TFA and lyophilized to give 20 mg (25%) of the product as the tri-TFA salt. MS (ES, m/z) 997 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.54 (t, J=6.0 Hz, 1H), 9.25 (d, J=2.6 Hz, 1H), 9.17 (d, J=9.1 Hz, 1H), 8.92-8.83 (m, 2H), 8.08 (s, 1H), 8.03 (dd, J=5.1, 1.4 Hz, 1H), 7.98 (dt, J=7.0, 1.9 Hz, 1H), 7.69 (s, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.58-7.46 (m, 3H), 7.46-7.35 (m, 2H), 6.27 (s, 1H), 4.74 (d, J=6.0 Hz, 2H), 4.68 (s, 2H), 4.23-4.12 (m, 2H), 4.02-3.82 (m, 4H), 3.74-3.50 (m, 22H), 3.25 (t, J=5.6 Hz, 2H), 2.93 (t, J=12.0 Hz, 2H), 1.27 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[CH2:19]=O>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:16]=[CH:15][C:14]2[O:17][CH2:19][N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:18]
Reactant: C=O
Reactant: Cc1c(Br)ccc(O)c1C(=O)Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc2c1C(=O)N(c1ccccc1)CO2
Temperature: 100 °C
Yield: 60 %

Procedure:
A mixture of 3-bromo-6-hydroxy-2-methyl-N-phenylbenzamide (Intermediate 16-1, 40 mg, 0.131 mmol) and paraformaldehyde (11.77 mg, 0.392 mmol) in TFA (1 mL) was heated at 100° C. for 4 h. The TFA was removed under vacuum, and the residue was diluted with EtOAc (80 mL), washed with NaHCO3 (aq) (10 mL), water (10 mL) and brine (10 mL), and dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) to give 6-bromo-5-methyl-3-phenyl-2H-benzo[e][1,3]oxazin-4(3H)-one (25 mg, 45%). 1H NMR (400 MHz, chloroform-d) δ 7.63 (1H, d, J=8.80 Hz), 7.37-7.50 (3H, m), 7.29-7.35 (2H, m), 6.81 (1H, d, J=8.80 Hz), 5.48 (2H, s), 2.80 (3H, s). Mass spectrum m/z 318, 320 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[Br:17][C:18]1[N:26]2[C:21]([CH:22]=[N:23][C:24](S(C)=O)=[N:25]2)=[CH:20][CH:19]=1.CN1CCCC1=O>>[Br:17][C:18]1[N:26]2[C:21]([CH:22]=[N:23][C:24]([NH:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=4[CH:12]=3)=[N:25]2)=[CH:20][CH:19]=1
Reactant: CS(=O)c1ncc2ccc(Br)n2n1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Solvent: CN1CCCC1=O
Product: COCCN1CCc2ccc(Nc3ncc4ccc(Br)n4n3)cc2CC1
Temperature: 135 °C
Yield: 62.5 %

Procedure:
Into a 30 ml, vial, [A] 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (0.242 g, 0.00110 mol), [B] 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.130 g, 0.000500 mol), and N-Methylpyrrolidinone (0.39 mL, 0.0041 mol) were added. The reaction mixture was heated at 135° C. for 7 hours. The reaction mixture was purified via ISCO column chromatography with EtOAc and methanol as eluant (5 to 20% methanol). The collected fractions afforded (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-amine as a yellow solid (130 mg, 65%). NMR 1H (CDCl3-d)-8.57 (s, 1H), 7.54 (s, 1H), 7.48 (dd, 1H, JJ=1.96, 6.04 Hz), 7.69 (s, 1H), 7.09 (d, 1H, J=8.04 Hz), 6.93 (s, 1H), 6.78 (d, 1H, J=4.72 Hz), 6.73 (d, 1H, J=4.72 Hz), 3.54 (t, 2H, J=5.68 Hz), 3.36 (s, 3H), 2.65-3.00 (m, 10H)
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1O[CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].NC(N)=[S:13]>O.C(O)C>[C:1]([O:6][CH2:7][CH:8]1[S:13][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: C=C(C)C(=O)OCC1CS1

Procedure:
Glycidyl methacrylate corresponding to the formula: ##STR10## is reacted with thiourea corresponding to the formula: ##STR11## at ambient temperature in a mixture of water and ethanol. The reaction gives 2,3-epithiopropyl methacrylate corresponding to the formula: ##STR12##
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:18]O>>[I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:18])=[O:8]
Reactant: CO
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(C)cc1C
Temperature: 25 °C
Yield: 88 %

Procedure:
A solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 10.0 g, 32.6 mmol, 90%) and sulfuric acid (10 mL) in methanol (100 mL) was stirred overnight at 80° C. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with of ethyl acetate (200 mL). The resulting mixture was washed with water (3×50 mL), sodium bicarbonate (aq. sat., 2×50 mL, caution: gas evolution), followed by brine (2×50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 9.2 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1C=CC=CC=1>[NH:1]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Nc1ccccc1)C(=O)OCC
Yield: 29.9 %

Procedure:
Aniline (18.6 g) was dissolved in dry benzene (125 ml), and diethyl bromomalonate (23.9 g) was added. The mixture was heated under reflux for 37 hours with stirring. The reaction mixture was washed with dilute hydrochloric acid to remove the unreacted aniline. The benzene layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate (10:1) as an eluent to give 7.5 g (yield 30%) of diethyl anilinomalonate having the following NMR data.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][C:15]3[C:16]([F:32])=[N:17][C:18]([NH:21][CH2:22][C:23]4[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=4)=[CH:19][CH:20]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=O.[CH3:33][NH2:34]>>[CH3:33][NH:34][C:3]([C:5]1[CH:6]=[C:7]2[C:13]([CH2:14][C:15]3[C:16]([F:32])=[N:17][C:18]([NH:21][CH2:22][C:23]4[C:24]([O:30][CH3:31])=[N:25][CH:26]=[C:27]([F:29])[CH:28]=4)=[CH:19][CH:20]=3)=[CH:12][NH:11][C:8]2=[N:9][CH:10]=1)=[O:2]
Reactant: CN
Reactant: COC(=O)c1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cnc4OC)nc3F)c2c1
Product: CNC(=O)c1cnc2[nH]cc(Cc3ccc(NCc4cc(F)cnc4OC)nc3F)c2c1
Temperature: 50 °C

Procedure:
3-{2-Fluoro-6-[(5-fluoro-2-methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid methyl ester (P-1693, 1 equivalent) is slurried with methylamine (2N in methanol, 15 equivalents) in a sealable vial, sealed and heated at 50° C. overnight. Additional methylamine (2N in methanol, 15 equivalents) is added and heated at 50° C. overnight. The reaction is concentrated under vacuum, the residue dissolved in tetrahydrofuran for purification on a C18 reverse phase column, eluting with 0-100% methanol (with 10% tetrahydrofuran)/water. Appropriated fractions are combined and concentrated under vacuum. The resulting material is triturated with ethyl acetate/heptane and filtered, washing with heptane. The solid is dried under vacuum to provide the desired compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(N(CC)CC)C>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccccc1N=C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 6 h

Procedure:
The preparation is carried out in the same way as in Example 20, from 1 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 1 ml of triethylamine and 0.97 ml of 2-methoxyphenyl isocyanate. After reacting for 6 hours at a temperature in the region of 20° C., the insoluble material is filtered and washed with water and then with isopropyl ether. 0.3 g of 8-[3-(2-methoxyphenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one are thus obtained in the form of a beige solid, the melting point of which is greater than 260° C. (Analysis C21H17N5 O3.0.76H2O, % calculated C: 65.11, H: 4.42, N: 18.08, % found C: 64.8, H: 4.3, N: 18.4).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1>O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1
Solvent: O
Product: O=C(Nc1ccc2ccc(Oc3ccc(Cl)cc3)nc2n1)c1ccccc1
Temperature: 0 °C
Yield: 23 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with benzoic acid (12.6 g), N,N'-carbonyldiimidazole (7.45 g) and 2-amino-7-(4-chlorophenoxy)-1,8-naphthyridine (12.6 g). The product obtained by precipitation in water (13 g; m.p. 100° C.) is purified by chromatography on a 4-cm-diameter column containing silica (0.040-0.063 mm; 200 g), eluting with methylene chloride and collecting 100-cc fractions. The fractions 10 to 25 are concentrated to 9/10 of the initial volume. After cooling for 2 hours at 0° C., the crystallized solid is separated by filtration, washed with diethyl ether (2×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-chlorophenoxy)-1,8-naphthyridin-2-yl]benzamide (4 g), m.p. 148° C., is obtained.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1>[Pd]>[CH2:1]1[CH:12]2[CH:4]([NH:5][C:6]3[C:7]([C:13]([NH:15][C@H:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[O:14])=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Agent: [Pd]
Product: COC(=O)[C@@H](C)NC(=O)c1cccc2c1NC1CCCC21

Procedure:
Following the procedure of method 1C, methyl (2R)-2-[(1,2,3,4-tetrahydrocyclopenta[b]indol-5-ylcarbonyl)amino]propanoate (4.9 mmol, 1.4 g) was hydrogenated using 5% Pd/C (1.5 g) and concentrated HCI (7 mL) in methanol (25 mL) to yield an oil (2.7 mmol, 0.77 9, 55%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS[C:21]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][N:29]=2)[N:24]=[CH:23][N:22]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:21]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][N:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ncnc2nccnc12
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncnc3nccnc23)CC1

Procedure:
EXAMPLE 86 was prepared from 4-aminomethyl-piperidine-1-carboxylic acid benzyl ester and 4-methylthio-pteridine (4-methylthio-pteridine was prepared according to A. A. Brown, D. J. Brown,h. C. S. Wood, J. Chem. Soc., 1954, 3832–3839): MS (m+1)=379.