Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:22]1([N:25]2[C:33]3[C:28](=[C:29]([O:37][CH3:38])[CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=3)[CH:27]=[CH:26]2)[CH2:24][CH2:23]1.Cl.[C:40]([CH2:43][NH:44][C:45]([C:47]1[CH:48]=[C:49]2[C:59](=[CH:60][CH:61]=1)[O:58][C:52]1([CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)[CH2:51][C:50]2=[O:62])=[O:46])(=[O:42])[NH2:41]>CN(C=O)C.O.CCN(CC)CC>[C:40]([CH2:43][NH:44][C:45]([C:47]1[CH:48]=[C:49]2[C:59](=[CH:60][CH:61]=1)[O:58][C:52]1([CH2:57][CH2:56][N:55]([C:34]([C:31]3[CH:32]=[C:33]4[C:28]([CH:27]=[CH:26][N:25]4[CH:22]4[CH2:23][CH2:24]4)=[C:29]([O:37][CH3:38])[CH:30]=3)=[O:36])[CH2:54][CH2:53]1)[CH2:51][C:50]2=[O:62])=[O:46])(=[O:42])[NH2:41]
Reactant: COc1cc(C(=O)O)cc2c1ccn2C1CC1
Reactant: NC(=O)CNC(=O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(=O)NCC(N)=O)ccc2O3)cc2c1ccn2C1CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Et3N (209 uL), HOBT (91.2 mg) and WSC (115 mg) were added to a suspension of 1-cyclopropyl-4-(methyloxy)-1H-indole-6-carboxylic acid (145 mg) and N-carbamoylmethyl-4-oxo-spiro[chroman-2,4′-piperidine]-6-carboxamide hydrochloride (354 mg) in DMF (3 mL), and the mixture was stirred overnight at 50° C. After cooled to room temperature, the mixture was diluted with water, and the formed solid was collected by filtration. The solid was dried and purified on silica gel preparative TLC (development: CHCl3/MeOH) to obtain the intended compound as colorless foam. 1H-NMR (400 MHz, DMSO-d6) δ: 8.84-8.72 (1H, m), 8.80-8.62 (1H, m), 8.33-8.29 (1H, m), 8.08 (1H, dd, J=8.7, 2.3 Hz), 7.35 (1H, s), 7.28 (1H, d, J=3.2 Hz), 7.23-7.16 (2H, m), 6.99 (1H, s), 6.58 (1H, d, J=1.0 Hz), 6.39 (1H, dd, J=3.2, 0.7 Hz), 4.40-4.02 (2H, br m), 3.87 (3H, s), 3.80-3.76 (2H, br m), 3.48-3.25 (4H, m), 2.98 (2H, s), 2.06-1.56 (2H, m), 1.09-1.01 (2H, m), 0.95-0.89 (2H, m); MS [M+H]+=531.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]2[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.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>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[S:6][C:5]([C@@H:7]([OH:21])[C@@H:8]3[N:12]([CH3:13])[C:11](=[O:14])[CH2:10][C@@H:9]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][CH:3]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(Br)s1
Reactant: OB(O)c1ccc(F)c(Cl)c1
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: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc(F)c(Cl)c2)s1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a solution of (±)-(4R*,5R*)-5-[(1S*)(5-bromo(2-thienyl))hydroxymethyl]-1-methyl-4-phenylpyrrolidin-2-one (300 mg, 0.82 mmol) in 1,2-dimethoxyethane (2.8 mL) was added 3-chloro-4-fluorobenzeneboronic acid (85.9 mg, 1.07 mmol), followed by a 1M Na2CO3 solution (2.2 mL). A catalytic amount of Pd(PPh3)4 was added and the reaction mixture was heated at the reflux temperature for 3 h, then allowed to cool to room temperature and poured onto a mixture of ice and CH2Cl2. The resulting mixture was extracted with CH2Cl2, dried (MgSO4) and concentrated under reduced pressure. The crude product was triturated (Et2O/ cyclohexane) to give (±)-(4R*,5R*)-5-{(1S*)[5-(3-chloro-4-fluorophenyl)(2-thienyl)]hydroxymethyl}-1-methyl-4-phenylpyrrolidin-2-one (235 mg, 69%): mp 194° C.; TLC (EtOAc) Rf 0.47
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([C:34]#[C:35][Si](C)(C)C)[C:25]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[F-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH2:31][CH2:32][OH:33])=[CH:28][CH:27]=[C:26]([C:34]#[CH:35])[C:25]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1F
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-fluoro-6-(2-hydroxy-ethoxy)-3-trimethylsilanylethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.08 mmol) prepared in example 184a in methanol (2 mL) was added KF (9.5 mg, 0.16 mmol) (Aldrich). The reaction mixture was stirred at room temperature for overnight. The solvent was removed and the residue was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[3-ethynyl-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:29][N:28]=[N:27][N:26]=2)=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>C(OCC)(=O)C.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>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[NH:26][N:27]=[N:28][N:29]=2)=[CH:23][C:24]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Cc1ccc(-c2nnn[nH]2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1ccc2c(N3CCOCC3)nncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnn[nH]2)cc1-c1ccc2c(N3CCOCC3)nncc2c1

Procedure:
6-Chloro-1-morpholinophthalazine (160 mg, 641 μmol), 5-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-tetrazole (220 mg, 769 μmol), and tetrakis(triphenylphosphine)palladium (74 mg, 64 μmol) were dissolved in ethanol (6408 μl, 641 μmol) and potassium carbonate—2 M in water (1282 μl, 2563 μmol) and heated to 80° C. for 4 h. The reaction mixture was diluted with 20 mL ethyl acetate, partitioned with ammonium chloride (saturated, aqueous), organic layer washed 2 times with 50 mL of ammonium chloride (saturated, aqueous) to give product in the aqueous layer, this was acidified with ca. 3 N HCl to pH 5. The aqueous layer was extracted with chloroform, organic layer separated, dried over sodium sulfate, concentrated in vacuo, and purified via HPLC to give title compound. MS (ES+): 374(M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:4][NH:5][C:6]([CH2:8][C@@H:9]1[CH2:27][CH2:26][C@@:12]2([O:16][C@:15]3([CH:21]4[CH2:22][CH:23]5[CH2:25][CH:19]([CH2:20]4)[CH2:18][CH:17]3[CH2:24]5)[O:14][O:13]2)[CH2:11][CH2:10]1)=[O:7])[NH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](N=[N+]=[N-])(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH3:1][C:2]([CH3:28])([CH2:4][NH:5][C:6]([CH2:8][C@@H:9]1[CH2:27][CH2:26][C@:12]2([O:16][C:15]3([CH:21]4[CH2:20][CH:19]5[CH2:25][CH:23]([CH2:22]4)[CH2:24][CH:17]3[CH2:18]5)[O:14][O:13]2)[CH2:11][CH2:10]1)=[O:7])[NH2:3]
Reactant: CC(C)(N)CNC(=O)C[C@H]1CC[C@]2(CC1)OO[C@]1(O2)C2CC3CC(C2)CC1C3
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(N)CNC(=O)C[C@H]1CC[C@@]2(CC1)OOC1(O2)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of OZ277 free base (0.46 g, 1.17 mmol), triphenylphosphine (0.77 g, 2.94 mmol), and trimethylsilyl azide (0.34 g, 2.95 mmol) in THF (20 ml) at 0° C. under N2 was added dropwise diisopropyl azodicarboxylate (0.71 g, 3.51 mmol). The mixture was slowly warmed to rt and stirred for 72 h. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined extracts were washed with saturated aqueous NaHCO3 (2×50 ml) and brine (50 ml), dried over MgSO4, filtered, and concentrated. To a solution of the residue CHCl3 (20 ml) was added a solution of p-toluenesulfonic acid monohydrate (0.22 g) in ethanol (10 ml). After evaporation of the solvents, the crude product was purified by crystallization from MeOH/CH2Cl2 (1:4) to afford trioxolane OZ373 (0.12 g, 17%) as a colorless solid. mp 220° C. dec; 1H NMR (500 MHz, CD3OD) δ1.28-1.38 (m, 2H), 1.38 (s, 6H), 1.65-2.09 (m, 21H), 2.37 (s, 3H), 2.86 (d, J=6.8 Hz, 2H), 4.58 (s, 2H), 7.23 (d, J=7.8 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H); 13C NMR (125.7 MHz, CD3OD) δ21.30, 23.79, 27.97, 28.37, 30.04, 30.87, 34.87, 35.77, 35.78, 36.04, 37.80, 37.88, 54.02, 55.39, 109.53, 112.40, 126.97, 129.81, 141.66, 157.09.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[C:22]([F:23])=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[C:14]([F:24])[CH:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[OH-].[Li+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:11][C:12]2[C:22]([F:23])=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[C:14]([F:24])[CH:13]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1cc(F)c(COc2cnc(OC)c(Cl)c2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncc(OCc2cc(F)c(C(=O)O)cc2F)cc1Cl
Temperature: 25 °C
Yield: 96.9 %

Procedure:
A solution of ethyl 4-((5-chloro-6-methoxypyridin-3-yloxy)methyl)-2,5-difluorobenzoate (Preparation 32, 112 mg, 0.313 mmol) in THF (3 mL) was treated with aqueous lithium hydroxide (1 M, 1.6 mL, 1.60 mmol) and stirred at room temperature. After 2% hours the reaction mixture was acidified with aqueous hydrochloric acid solution (2 N, 15 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over magnesium sulfate and evaporated to afford the title compound as a white solid (100 mg, 97%).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH2:35])[CH2:23][CH3:24])[CH3:21].C(OC(C)C)(C)C>O>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][CH2:34][NH:35][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CCCN
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC1CCCCN1CCCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 54 %

Procedure:
Prepared analogously to Example 2 from 5-chlorocarbonyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 3-[2-[(diethylamino)methyl]-piperidin-1-yl]propanamine in a yield of 54% of theory, m.p. 148.0°-149.5° C. (diisopropylether). Soluble in water.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](OC)=[O:15]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14](=[O:15])[N:11]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: NC(=S)NC1CC2CCC1C2
Product: O=C1N=C(NC2CC3CCC2C3)SC1c1ccccc1

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and methyl alpha-bromophenylacetate according to Method C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][NH:6][C:5](=[O:9])[CH:4]=1.[H-].[Na+].[CH3:12][O:13][C:14](=[O:23])[CH:15](Br)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH3:12][O:13][C:14](=[O:23])[CH:15]([N:6]1[C:5](=[O:9])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[N:7]1)[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: COc1cn[nH]c(=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)n1ncc(OC)cc1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A solution of 5-methoxy-2H-pyridazin-3-one (500 mg, 3.96 mmol) in tetrahydrofuran (19.8 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (190 mg, 4.75 mmol). The reaction was stirred at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 1.02 g, 4.36 mmol). The reaction was then warmed to 50° C. where it stirred overnight. After this time, the reaction was cooled to 25° C., was poured into water (100 mL) and was extracted into ethyl acetate (3×75 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 40% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (488 mg, 43%) as a clear oil; ES+-HRMS m/e calcd for C14H20N2O4 [M+H+] 281.1496 found 289.1495. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.16 (m, 2H), 1.33-1.64 (m, 6H), 1.63-1.78 (m, 1H), 1.89-2.03 (m, 1H), 2.16 (ddd, J=13.9, 10.9, 5.4 Hz, 1H), 3.61 (s, 3H), 3.82 (s, 3H), 5.39 (dd, J=10.7, 4.4 Hz, 1H), 6.32 (d, J=2.7 Hz, 1H), 7.84 (d, J=2.7 Hz, 1H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The mixture of 2.2 g of 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid and 22 ml of 2N aqueous sodium hydroxide is refluxed for 1 hour under nitrogen. After cooling it is filtered, the filtrate acidified with glacial acetic acid to pH = 4. The precipitate formed is filtered off and recrystallized from 50% aqueous ethanol, to yield the 4-(4-aminophenylmercapto-)-3-benzylamino-5-sulfamoylbenzoic acid melting at 254°-256°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19]C=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C1(CCN2CCN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)CC1>>[CH:21]1([CH2:22][CH2:17][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:23])[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CCC3CC3)C2=O)nc1C
Product: Cc1nc(N2CCN(CCC3CC3)C2=O)sc1C(=O)O
Yield: 88 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(2-cyclopropylethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 88% yield: 1H NMR (300 MHz, DMSO-d6) δ 4.20-3.04 (m, 6H), 2.45 (s, 3H), 1.50-1.41 (m, 2H), 0.78-0.54 (m, 1H), 0.43-0.28 (m, 2H), 0.10-0.96 (m, 2H); MS (ES+) m/z 296.2 (M+1).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[CH:5]=[N+:6]2[O-].[NH4+:19].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:14]3[O:15][CH2:16][CH2:17][CH2:18][C:13]3=[N:12][C:4]=1[C:5]([NH2:19])=[N:6]2
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc1n2OCCC1
Reaction time: 2 h

Procedure:
A solution of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (0.364 g, 1.51 mmol) in 10 mL of dichloromethane was treated with 7 mL of concentrated aqueous NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (0.34 g, 1.78 mmol) was carefully added. Rapid stirring was continued for 2 hours. The reaction mixture was then diluted with more dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure. The solid was dissolved in hot CH3CN. The resulting crystals were filtered off and dried to give 0.0578 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid, dec. 229-234° C. MS (APCI) m/z 241 (M+H)+; Anal. calcd for C13H12N4O: C, 64.99; H, 5.03; N, 23.32. Found: C, 64.81; H, 4.74; N, 23.44.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.C(C1C2NC(=O)CC(=O)N(C3C=CC(NC(=O)OC(C)(C)C)=CC=3)C=2C=CC=1)C.[Br:54][C:55]1[CH:56]=[C:57]([S:61](Cl)(=[O:63])=[O:62])[CH:58]=[CH:59][CH:60]=1>N1C=CC=CC=1>[Br:54][C:55]1[CH:56]=[C:57]([S:61]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)(=[O:63])=[O:62])[CH:58]=[CH:59][CH:60]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: c1ccncc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3cccc(Br)c3)cc2)c2ccc3ccccc3c2N1
Yield: 60 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3) (15 mg, 0.047 mmol), and 3-bromobenzenesulfonyl chloride (24 mg, 0.095 mmol) were treated by heating in pyridine (1.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (15 mg, yield 60%) as slightly brown amorphous.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:49](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:49])[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1)C(C)(C)C
Reaction time: 2.75 h

Procedure:
Analogously to Example 37f), 130 ml of 4 M HCl in dioxane are added to 4.4 g (6.94 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 7 ml of DMF. After 2.75 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.44 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.47; FAB MS (M+H)+ =534.
Reaction SMILES: [OH-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[C:7]([O:11][C:12]([NH:14][C@H:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][C@H:16]1[OH:26])=[O:13])([CH3:10])([CH3:9])[CH3:8].C1(C)C=CC=CC=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CCOC(C)=O.O>[CH2:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[C@H:16]([O:26][CH2:5][CH:4]=[CH2:3])[CH2:17]1)=[O:22])[CH3:25]
Reactant: C=CCBr
Reactant: CCOC(=O)N1CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCO[C@@H]1CN(C(=O)OCC)CC[C@@H]1NC(=O)OC(C)(C)C
Yield: 86 %

Procedure:
A 50% aqueous solution of sodium hydroxide (3 ml) was added to a suspension of allyl bromide (693 mg, 5.70 mmol), cis(±)ethyl 4-[(tert-butoxycarbonyl)amino]-3-hydroxypiperidine-1-carboxylate (reference: C. H. Lee et al. Syn. Commun., 2001, 31, 1081), (750 mg, 2.6 mmol), benzyltriethylammonium chloride (4 mg, cat.) and toluene (8 ml). The resultant mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (150 ml) and water (35 ml). The organic phase was separated and the aqueous phase was back extracted with EtOAc (2×30 ml). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography (hexane/EtOAc, 3:2) to yield 734 mg of the title compound. MS (ES)(M+H): 329. for C16H28N2O5; NMR: 1.28 (t, 3H), 1.47 (s, 9H), 1.68 (m, 2H), 2.88 (brt, 2H), 3.50 (m, 1H), 3.68 (m, 1H), 3.90 (m, 1H), 4.00-4.45 (m, 3H), 4.10 (q, 2H), 4.92 (brs, 1H), 5.20 (m, 2H), 5.86 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.O1CCC[CH2:18]1>CN>[Cl:1][C:2]1[N:11]=[C:10]([NH:12][CH3:18])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1CCOC1
Agent: CN
Product: CNc1nc(Cl)nc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-4-amino-6,7-dimethoxyquinazoline (2.0 g) in tetrahydrofuran (100 ml), methylamine was introduced over a period of 15 min. The reaction mixture was stirred for 2 hr at room temperature and evaporated. The residue was triturated with cold aqueous sodium carbonate solution and the solid was washed and dried to give 1.769 g of 2-chloro-4-methylamino-6,7-dimethoxyquinazoline. A portion of this compound was crystallized from methylene chloride-hexane to mp 216°-217° C.; ir (nujol mull) 3470 cm-1 ; nmr (DMSO-d6) δ 3.0 (d, 3H), 3.9 (s, 6H), 7.05 (s, 1H), 7.55 (s, 1H) and 8.3 (broad s, 1H); and Anal. Calcd for C11H12ClN3O2 : C, 52.07% H, 4.77% N, 16.56% and Found: C, 51.95% H, 4.70% N, 16.45%.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:24][O:23][C:20]1[N:21]=[CH:22][C:17]([N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:18][CH:19]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(Br)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Yield: 5.7 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 5-bromo-2-methoxypyridine (0.752 g, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified reverse phase HPLC to yield 5-(6-Methoxy-pyridin-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 8.20 (s, 1H), 7.74 (d, 1H), 7.32 (s, 1H), 7.0 (m, 3H), 4.78 (m, 1H), 4.40 (m, 1H), 4.0 (s, 3H), 3.82 (m, 1H), 3.60 (m, 1H), 3.16 (s, 3H), 3.10 (m, 1H), 2.98 (m, 1H), 2.42 (s, 3H).