Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([C@@H:31]([NH:33]C(=O)OC(C)(C)C)[CH3:32])=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41]>ClCCl.O1CCOCC1>[ClH:41].[C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([C@@H:31]([NH2:33])[CH3:32])=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-tert-butyl (1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethyl)carbamate (0.251 g) in dichloromethane (20 mL) was added 4.0 M HCl in dioxane (2 mL). The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then diluted with ether (20 mL). The product was removed by filtration under reduced pressure and dried to give (S)-1-(4-(2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)ethanamine hydrochloride as a yellow solid (0.215 g, 98% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.83 (br. s, 1 H), 8.69 (br. s, 3H), 8.16 (dd, JA=4.7 Hz, JB=1.6 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.52-7.44 (m, 3H), 7.40-7.30 (m, 3H), 7.28 (d, J=8.2 Hz, 2H), 7.19 (t, J=7.6 Hz, 1H), 6.95-6.91 (m, 1H), 6.82-6.77 (m, 1H), 4.43 (quint., J=6.1 Hz, 1H), 1.52 (d, J=6.7 Hz, 3H); LCMS: 430 [M+H]; Calc. for C28H23N5.3.5HCl.0.05 dioxane.0.35 diethylether: C, 60.52; H, 5.22; N, 11.92. Found C, 60.57; H, 5.67; N, 12.02.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6].ClC(OCC)=O.C(N(CC)CC)C.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.[Cl-].[Na+]>C1COCC1>[CH:22]1([NH:25][C:1](=[O:8])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH3:6])[CH2:24][CH2:23]1
Reactant: CCC/C=C\C(=O)O
Reactant: NC1CC1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC/C=C\C(=O)NC1CC1
Yield: 77 %

Procedure:
3Z-Hexenoic acid 1 eq, ethyl chloroformate 1.1 eq, triethylamine 1.2 eq, cyclopropylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=77%. 0.49 ppm (m, 2H), 0.75 ppm (m, 2H), 0.98 ppm (t, 3H, J=7.48 Hz), 2.05 ppm (d, 2H, J=0.97 Hz, of pentet, J=7.46 Hz), 2.70 ppm (octet, 1H, J=3.59 Hz), 2.98 ppm (d, 2H, J=7.46 Hz), 5.46-5.52 ppm (m, 1H), 5.58-5.66 ppm (m, 1H), 6.19 ppm (br. s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2([C:23]3[CH:31]=[C:30]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH:29]=[CH:28][C:24]=3[C:25](O)=[O:26])[CH2:21][CH:20]3[CH2:22][CH:17]2[CH2:18][CH2:19]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:44][CH2:45][C:46]1[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:10]1([C:16]2([C:23]3[CH:31]=[C:30]([O:32][CH2:33][C:34]4[CH:43]=[CH:42][C:41]5[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:35]=4)[CH:29]=[CH:28][C:24]=3[C:25]([NH:44][CH2:45][C:46]3[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=3)=[O:26])[CH2:21][CH:19]3[CH2:18][CH:17]2[CH2:22][CH2:20]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2

Procedure:
DIPEA (3.0 equiv.) is added to a stirred solution of 2c (1.0 equiv.), 3-(aminomethyl)pyridine (1.0 equiv.) and HATU (1.5 equiv.) in DMF at ambient temperature. After completion of reaction, the reaction mixture is poured into water and extracted three times with EtOAc. The combined organic extracts are washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The crude residue can be purified according to the method described in Step E.
Reaction SMILES: [CH3:1][C:2](C)=[CH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:28])[C:14]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[OH:15])[CH2:8][CH2:7]1.Cl.Cl.N[CH:33]1[CH2:38]CN(CC2CCCCCC2)C[CH2:34]1>>[CH:4]1([CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:28])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:15])[CH2:10][CH2:11]2)[CH2:38][CH2:33][CH2:34][CH2:1][CH2:2][CH2:3]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2cccc(F)c2)C2CCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1cccc(F)c1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-(3-fluorophenyl)-2-cyclopentyl-2-hydroxyacetic acid obtained in Example 53 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]3)=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=2)=[O:10])=[C:4]([F:31])[CH:3]=1.[CH2:32]([O:34][C:35]1[C:36]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)=[N:37][CH:38]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:40]=1)[CH3:33].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:32]([O:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH2:24]4)=[C:14]([C:27]([F:30])([F:28])[F:29])[CH:13]=3)=[O:10])=[C:4]([F:31])[CH:3]=2)[CH:38]=[N:37][C:36]=1[O:50][CH2:51][C:52]1[CH:53]=[CH:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)[CH3:33]
Reactant: CCN1CCN(Cc2ccc(NC(=O)Cc3ccc(Br)cc3F)cc2C(F)(F)F)CC1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(CN4CCN(CC)CC4)c(C(F)(F)F)c3)c(F)c2)cnc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
A suspension of 2-(4-bromo-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (413 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL) was added to a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (317 mg, 0.822 mmol) in 1,4-dioxane (3 mL) and H2O (1 mL). PdCl2(dppf) (60.2 mg, 0.082 mmol) and Cs2CO3 (536 mg, 1.644 mmol) were added and the mixture was at 110° C. for 30 min in a microwave. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=1/1, Rf=0.5) to yield a light yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)acetamide (405 mg, 0.595 mmol, 72.4% yield): 1H NMR (400 MHz, CD3OD) δ 8.02-7.87 (m, 2H), 7.82-7.64 (m, 2H), 7.60-7.30 (m, 6H), 6.98-6.80 (m, 2H), 5.34 (s, 2H), 4.18-4.04 (m, 2H), 3.84-3.72 (m, 4H), 3.68-3.57 (m, 2H), 2.91-2.38 (m, 10H), 1.47-1.31 (m, 3H), 1.14 (s, 3H); ES-LCMS m/z 681.3 (M+H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Br:19]N1C(=O)CCC1=O>CN(C)C=O>[Br:19][C:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]2[CH2:3][O:1]2)=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CN(C)C=O
Product: Brc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Yield: 10 %

Procedure:
A solution of 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.750 g, 3.13 mmol) and N-bromosuccinimide (0.57 g, 3.2 mmol) in 10 mL dry dimethylformamide (DMF) was stirred at ambient temperature for 48 hours. The reaction mixture was partitioned with EtOAc and H2O. The organic phase was washed with H2O and dried with Na2SO4. The solvent was removed (rotovap) and the residue purified by flash chromatography (hexane-EtOAc 5:1) afforded 0.10 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1cccc(O)c1O
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
To a solution of 3-nitrobenzene-1,2-diol (600 mg) in methanol (6 ml) was added 10% palladium on carbon (60 mg), and the mixture was stirred for 3 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 3-aminobenzene-1,2,-diol (470 mg).
Reaction SMILES: [NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([NH:35][CH2:36][C:37]([O:39]CC1C=CC=CC=1)=[O:38])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[H][H]>C(O)C.[Pd]>[NH:1]([C:47]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[O:48])[C@H:2]([C:7]([NH:9][C@H:10]([C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:33]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34])[CH2:29][CH:30]([CH3:31])[CH3:32])=[O:26])[CH2:21][C:22](=[O:24])[NH2:23])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)O
Reaction time: 3 h
Yield: 71.1 %

Procedure:
10% Pd/C (300 mg) was added to the compound [31] (2.8 g, 3.8 mM) dissolved in ethanol (100 ml) and hydrogen gas was passed therethrough at room temperature for 3 hours. Insoluble materials precipitated in the reaction mixture were filtered and washed with DMF. The filtrate was concentrated in vacuo. Ethanol-ether was added to the residue, and the precipitate was collected by filtration and dried to obtain the product [32].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 (2.4 g, 11.8 mmol) in 60 ml of ethyl acetate was added 60 ml of saturated K2CO3. To this biphasic solution was added benzyl chloroformate (2.03 ml, 14.23 mmol) dropwise. After stirring at room temperature for 3 hours the layers were separated and the organic layer dried over MgSO4, filtered, and the solvents removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[N:6]([C:14]([CH3:19])([CH3:18])[C:15]([O-:17])=O)=[N:7][C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=O.C[O-].[Na+].O>CO>[N:7]([C:8]([CH3:12])([CH3:13])[C:9]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:11])=[N:6][C:14]([CH3:19])([CH3:18])[C:15]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:17]
Reactant: CC(C)CN
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)CNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCC(C)C
Temperature: 10 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
34.9 Grams of isobutylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol is dropwise added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 56.4 g (yield 83%) of 2,2'-azobis [N-(2 -methylpropyl)-2-methyl propionamide] as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]([CH2:14][CH:15]([OH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][CH:12]([CH2:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: CCCCC(O)CC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)CC(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.9 %

Procedure:
A solution of oxalyl chloride (4.2 ml, 49 mmol) in dry DCM (200 ml) was cooled to -78° C. under argon. Dimethylsulphoxide (6.9 ml, 98 mmol) was added slowly and the mixture stirred for 5 min. 2-Methyloctan-4-ol (6.4 g, 44 mmol) was added and the mixture stirred for 20 min. Triethylamine (30.7 ml, 0.22 ml) was added and after 5 min. the mixture was allowed to warm up to room temperature. Water (100 ml) was added, the organic layer separated and the aqueous layer extracted with DCM. The combined organic extracts were dried over anhydrous magnesium sulphate, filtered and concentrated to give 2-methyloctan-4-one (5.0 g, 79%) as a waxy oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[CH:6][C:3]=1[CH:4]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:4]/[C:3]2[CH:6]=[C:7]([F:11])[C:8]([F:10])=[CH:9][C:2]=2[F:1])/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1cc(F)c(F)cc1F
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cc(F)c(F)cc2F)cc1OC
Yield: 25.1 %

Procedure:
2,4,5-Trifluorobenzaldehyde (160 mg) and 3,4-dimethoxybenzyl cyanide (177 mg) were subjected to condensation in accordance with process B of (production process 2), to thereby produce the target product (80 mg, yield: 26%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([I:10])[C:3]=1[NH2:4].[N+:11]([O-])([OH:13])=[O:12].C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([I:10])[C:3]=1[NH:4][N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Nc1c(Br)cc(Cl)cc1I
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])Nc1c(Br)cc(Cl)cc1I
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2-bromo-4-chloro-6-iodoaniline (18.05 mmole, 6.0 g) in 200 ml of glacial acetic acid is added dropwise, 90% nitric acid (173.52 mmole, 8.1 ml). The precipitated salt is observed, while continued stirring with cooling for 0.5 hour. Acetic anhydride (8.1 ml) is added dropwise with cooling. The solution darkens and becomes homogeneous. The cooled solution is poured into 600 ml of ice water, the precipitate is filtered, washed with water, then dissolved in 10% sodium bicarbonate (300 ml). The filtrate is extracted with methylene chloride (3×100 ml), and the combined methylene chloride extracts are washed with water (3×100 ml). The methylene chloride layer is extracted with 10% sodium bicarbonate (3×100 ml), and both of the bicarbonate solutions are combined, then washed with methylene chloride until the bicarbonate layer is colorless. The bicarbonate solution is cooled in an ice bath, then acidified with 15% HCl. The precipitated product is filtered, washed with water, then dried in vacuo. Recrystallization from hot hexane yield 4.22 g of product melting at 121°-123° C.(dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C#CCCCO)ccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)n1ccc2cc(CCCCCO)ccc21
Yield: 97.1 %

Procedure:
2.85 g (9.5 mmol) 5-(5-Hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butyl ester in 100 ml MeOH were subjected to hydrogenation with 300 mg 10%Pd/C to yield 2.8 g 5-(5-Hydroxy-pentyl)-indole-1-carboxylic acid tert-butyl ester as colorless oil, MS: 303 (M). To the crude material in 60 ml CH2Cl2, 0.87 ml (11 mmol) methanesulfonyl chloride and 3.8 ml (27 mmol) triethyl amine were added at 0° C. The solution was stirred at RT for 1 h.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:34])[C@@H:16]([NH:26]C(=O)OC(C)(C)C)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:8]([C@@:10]2([CH3:13])[CH2:12][O:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:15]([NH:14][C@@H:7]([CH2:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[C:8]([C@@:10]1([CH3:13])[CH2:12][O:11]1)=[O:9])=[O:34]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.5 h

Procedure:
To tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.99 g, 2.1 mmol) was added DCM (5 mL) and TFA (5 mL). The mixture was allowed to stand at ambient temperature for 30 min then it was concentrated to provide crude (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (quant.) and carried forward without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[K+].[Cl-].[K+]>C(O)C>[CH2:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)[CH:9]1[O:11][CH2:10]1
Reactant: C1CNCCN1
Reactant: ClCC1CO1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C1CN(CC2CO2)CCN1

Procedure:
Piperazine (86.15 g., one mole) and ethanol (150 g.plus 1.5 g. water) were placed in a one liter 3-neck flask equipped with a stirrer, thermometer, dropping funnel and condenser. The mixture was stirred until a complete solution was obtained and then epichlorohydrin (92.53 g., one mole) was added dropwise while maintaining the temperature below 25° C., by means of an ice bath. After addition of the epichlorohydrin was complete, the temperature was maintained below 25° C. for an additional 30 minutes. Then a solution of 56.11 g. (1 mole) of potassium hydroxide in 225 g. of ethanol was added over a period 30 minutes while maintaining the temperature below 25° C. After cooling to 15° C. the potassium chloride which had formed during the reaction was filtered from the mixture and the filtrate concentrated to one-half its volume by stripping under vacuum. One liter of ethyl acetate was then added to the residual filtrate. The N-glycidylpiperazine oligomer precipitated as a white solid. The resultant slurry was filtered after standing several hours. The N-glycidylpiperazine oligomer collected on the filter after drying in vacuo at room temperature amounted to 119 grams, 83.8% of the theoretical yield. Elemental analysis indicated: %C, 56.09; %H, 9.55; %N, 18.55; %O, 15.77. The number average molecular weight as determined by vapor pressure osmometry was 705. This data corresponds to the formula: ##STR5##
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[O:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1>C(O)(C)C>[Br:8][C:6]1[N:7]=[C:2]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:15][CH2:16][O:11][CH2:12][CH2:13]3)=[CH:22][CH:21]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Temperature: 90 °C
Yield: 85.1 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 3,5-dibromo-1-methylpyrazin-2(1H)-one (1.97 g, 7.4 mmol), 4-morpholinobenzenamine (1.97 g, 11.1 mmol), and isopropanol (25 mL). The system was evacuated and then refilled with N2. It was heated at 90° C. for 16 h. Then, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 122a (2.3 g, 85%). LCMS: [M+H]+ 365.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:29][CH:26]([CH3:28])[CH3:27])=[CH:16][CH:17]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[CH:7][CH:8]=2)[C:3]1=[O:25]
Reactant: COc1ccc2cc(-c3ccc(OCC4CO4)cc3)n(C)c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2cc(-c3ccc(OCC(O)CNC(C)C)cc3)n(C)c(=O)c2c1
Yield: 63 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example (1b) from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine at a reaction temperature of 50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(Cl)cccc4Cl)cc3)c2cc1OC
Yield: 95.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2,6-dichlorophenyl isocyanate (125 mg) was added, and the admixture was refluxed with heat for 12 minutes. The separated crystals were filtered and then washed with toluene to obtain 81 mg of the title compound (yield: 96%).