Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][OH:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([N:10]([CH2:14][CH3:15])[CH2:11][CH2:12][O:13][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26]
Reactant: CCN(CCO)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CCOS(C)(=O)=O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester, methanesulfonyl chloride and triethylamine in methylene chloride was stirred at rt until all starting material were consumed. The mixture was quenched with water, brine and extracted with methylene chloride. The organic layer was dried and concentrated to dryness. The residue was purified through silica gel column chromatography to give the title compound. 1H NMR(CDCl3) d 6.83(s,2H), 6.25(s,1H), 4.34(t,2H), 3.86(s,3H), 3.6(t,2H), 3.38(t,2H), 3.09s,3H), 2.25(s,3H), 2.20(s,3H), 2.04(s,6H), 1.18(t,3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C1CCNc2cc(Cl)ccc21
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12

Procedure:
17.8 millimols, representing a yield (determined) of 99% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted, and of 96.3% relative to the 1-diethylamino-4-aminopentane converted, and
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1([S:25][CH3:26])[CH2:16][N:15]([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:14]1=[O:24].C(N(CC)CC)C.[N+:34]([C:37]1[CH:55]=[CH:54][C:40]([CH2:41][O:42][C:43]([CH:45]([C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:46](Cl)=[O:47])=[O:44])=[CH:39][CH:38]=1)([O-:36])=[O:35]>ClCCl>[Si:17]([N:15]1[CH2:16][C:13]([S:25][CH3:26])([NH:12][C:46](=[O:47])[CH:45]([C:43]([O:42][CH2:41][C:40]2[CH:54]=[CH:55][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[O:44])[C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)[C:14]1=[O:24])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CSC1(N)CN([Si](C)(C)C(C)(C)C)C1=O
Reactant: O=C(Cl)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CN([Si](C)(C)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
A solution of (23) (418 mg) in dry dichloromethane (10 ml) containing triethylamine (222 mg) at 0° C. was treated with a solution of 2-(p-nitrobenzyloxycarbonyl)-2-thien-3-ylacetylchloride (407 mg) in dry dichloromethane (5 ml). The mixture was stirred at 0° C. for 15 minutes, then allowed to warm to room temperature. After 1 hour the mixture was washed successively with sat.NaHCO3, water, dilute HCl, water and brine. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the residue on silica gel gave the product (39) (496 mg) as a foam.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][C:12](=O)[NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1.[Na]>O1CCOCC1>[CH3:5][O:6][C:7]1[C:18]([O:19][CH3:20])=[CH:17][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CCNCC2

Procedure:
A solution of glacial acetic acid (1.8 g) in dioxan (10 ml) is added dropwise to a suspension of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (1.3 g, 6 mmol) and sodium borohydridel (1 g, 3 mmol) in dioxan (20 ml), refluxed for 3 hours, concentrated by evaporation and decomposed with water. The mixture is extracted twice with methylene chloride, the extract is concentrated by evaporation and the residue is taken up in ether. After filtration the ether is eliminated in vacuo.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C(O)C>[CH2:12]([NH:16][CH:3]1[CH2:2][S:1](=[O:10])(=[O:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]1=2)[CH2:13][CH2:14][CH3:15]
Reactant: O=S1(=O)C=Cc2ccccc21
Reactant: CCCCN
Solvent: CCO
Product: CCCCNC1CS(=O)(=O)c2ccccc21
Yield: 112.2 %

Procedure:
9.0 g (54 mmol) of benzothiophene 1,1-dioxide and 7.9 g (108 mmol) of n-butylamine were suspended in 130 ml of ethanol, and the mixture was heated at reflux temperature for 3 h. The reaction mixture was concentrated under reduced pressure, giving 14.5 g of butyl-(1,1-dioxo-2,3-dihydro-1H-benzo[b]thiophen-3-yl)-amine as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.4 %

Procedure:
A suspension of 18 (2.91 g, 8.68 mmol), Cs2CO3 (4.25 g, 13.02 mmol) and DMF (anhydrous, 40 mL) was stirred at room temperature for 1.5 h. To the mixture was then added methyl iodide (0.83 mL, 13.02 mmol), and stifling was continued for an additional 3 h at the ambient temperature. The mixture was then partitioned between water (150 mL) and dichloromethane (150 mL), aqueous layer was separated and washed with dichloromethane (3×300 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired methyl ester 19 (3.41 g, quant yield): 1H NMR (500 MHz, CDCl3) δ 1.26 (m, 12H), 1.47 (m, 2H), 1.52 (m, 2H), 2.28 (m, 2H), 3.16 (m, 2H), 3.66 (s, 3H), 5.10 (s, 2H), 7.32 (m, 5H); m/z (ESI) 350 [M+H]+.
Reaction SMILES: C(O)=O.[C:4]([C:6]1[CH:7]=[C:8]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH2:23][CH2:24][N:25]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH2:26]4)[N:17]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:5].[Li+].[OH-].Cl.C(Cl)[Cl:41]>C1COCC1.CO.O>[ClH:41].[C:4]([C:6]1[CH:7]=[C:8]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:22]=3[CH2:23][CH2:24][N:25]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:26]4)[N:17]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:5]
Reactant: COC(=O)CCN1CCc2c(cccc2-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)C1
Reactant: ClCCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCN(CCC(=O)O)C4)no2)cc1C#N

Procedure:
A solution of methyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-3,4-dihydro-2(1H)-isoquinolinyl]propanoate formic acid salt (Preparation 6, 5.9 mg, 0.0132 mmol) and LiOH (0.15 mg) in THF-MeOH-water (300 μl, 300 μl, 100 μl) was irradiated to 100° C. for 3 min in the microwave. 2M aqueous HCl (1 ml) and DCM (2 ml) were added sequentially, and a precipitate formed. Filtration gave the title compound as a white solid (6.5 mg, quant.). 1H NMR (400 MHz, d6-DMSO) δ 12.71 (1H, br s), 11.41 (1H, br s), 8.53 (1H, d), 8.41 (1H, dd), 8.05 (1H, d), 7.57 (1H, d), 7.53 (1H, t), 7.46 (1H, d), 4.99 (1H, sept), 4.53 (2H, br s), 3.46-3.43 (4H, m), 3.65 (2H, br s), 2.98 (2H, t), 1.39 (6H, d); m/z (ES) 433 [M+H+].
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.[NH4+]>>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[N:4][C:5]3[C:6]4[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=4[CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:24][CH2:23]1
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Agent: [NH4+]
Product: c1cnc(N2CCN(c3cc4c(nn3)-c3ccccc3CC4)CC2)nc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
A mixture of comprising about 0.01 mol of 3-chloro-5,6-dihydrobenzo[h]cinnoline, about 0.05 mol of 1-(2-pyrimidyl)piperazine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at 130° C. for 48 h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded golden yellow crystals, yield 87.0%; HPLC: 96.6% purity; HRMS calculated 344.1744, found 344.1738; 1H NMR (CDCl3): d 8.452 (d, J=7.5, 1H), 8.346 (d, J=4.5, 2H), 7.200-7.364 (m, 3H), 6.794 (S, 1H), 6.542 (t, J=4.5, 1H), 3.999 (t, J=5.0, 4H), 3.808 (t, J=5.0, 4H), 2.909 (s, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([P:21]([O:26]CC)(=[O:25])[O:22]CC)[P:13]([O:18]CC)(=[S:17])[O:14]CC)[CH:6]=[CH:5]2.C[Si](Br)(C)C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([P:21]([OH:26])(=[O:22])[OH:25])[P:13]([OH:14])(=[S:17])[OH:18])[CH:6]=[CH:5]2
Reactant: CCOP(=O)(OCC)C(c1ccc2cc(O)ccc2c1)P(=S)(OCC)OCC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C(c1ccc2cc(O)ccc2c1)P(O)(O)=S
Yield: 84 %

Procedure:
Following the same method as in Example 2, 7.15 g (15 mmol) of the tetraethyl 6-hydroxy-2-naphthylthiomethanediphosphonate obtained in Example 5 was treated with trimethylsilyl bromide, and then hydrolyzed to obtain 4.21 g of the title compound as white crystals.
Reaction SMILES: O=[C:2]1[CH:11]([C:12]([O:14]C)=O)[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:20][C:18]1[N:19]=[C:12]([OH:14])[C:11]2[CH2:10][CH2:9][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[C:2]=2[N:17]=1
Reactant: N=C(N)N
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(O)c2c(n1)C1(CCCC1)CCC2

Procedure:
A solution of Example 10B (4.5 g, 21.4 mmol), guanidine hydrochloride (6.13 g, 64.2 mmol), and potassium carbonate (9.46 g, 68.5 mmol) in N,N-dimethylformamide (30 mL) was heated at 105-110° C. for 3 hours. The mixture was then filtered through a layer of diatomaceous earth, and the filter pad was washed with a small amount of N,N-dimethylformamide. Approximately two volumes of water were then added, and the pH of the resulting mixture was adjusted to pH 6-7 with acetic acid. The precipitate was collected, washed with water, and dried under vacuum to provide the title product. 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.61 (m, 1H), 5.98-6.08 (m, 2H), 2.20 (t, 2H), 1.95-2.04 (m, 2H), 1.68-1.76 (m, 2H), 1.61-1.68 (m, 2H), 1.48-1.58 (m, 4H), 1.34-1.45 (m, 2H); MS (DCI+) m/z 220 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[CH:17][C:18]([O:25][CH3:26])=[C:19]3[C:23]=2[CH2:22][C:21]([CH3:24])=[CH:20]3)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:32][C:33]1[CH:34]([Si:54](Cl)([CH3:56])[CH3:55])[C:35]2[C:40]([CH:41]=1)=[C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:38]([O:48][CH3:49])=[C:37]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:36]=2.O>CCOCC.C([Cu])#N>[CH3:32][C:33]1[CH:34]([Si:54]([CH:20]2[C:19]3[C:23](=[C:15]([C:7]4[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=4)[CH:16]=[CH:17][C:18]=3[O:25][CH3:26])[CH:22]=[C:21]2[CH3:24])([CH3:55])[CH3:56])[C:35]2[C:40]([CH:41]=1)=[C:39]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:38]([O:48][CH3:49])=[C:37]([C:50]([CH3:51])([CH3:52])[CH3:53])[CH:36]=2
Reactant: COc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2c1C=C(C)C2
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)C=C(C)C2[Si](C)(C)Cl
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: COc1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2c1C([Si](C)(C)C1C(C)=Cc3c1cc(C(C)(C)C)c(OC)c3-c1ccccc1)C(C)=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of 12.3 g (35.3 mmol) of 7-(3,5-di-tert-butylphenyl)-4-methoxy-2-methyl-1H-indene in 200 ml of ether 14.2 ml (35.5 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −50° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 150 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution of 13.6 g (35.3 mmol) of (2-methyl-4-phenyl-5-methoxy-6-tert-butyl-1H-inden-1-yl)(chloro)dimethylsilane in 200 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was additionally washed by dichloromethane. The combined organic elute was evaporated to dryness and dried in vacuum. This procedure gave 24.9 g of a yellowish glass. This product of ca. 90% purity was further used without an additional purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])=[CH:10][C:5]=2[N:4]([CH3:17])[C:3]1=[O:18].O.Cl.C(=O)(O)[O-:22].[Na+]>CO.[Fe].O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12](=[O:22])[CH3:13])=[CH:10][C:5]=2[N:4]([CH3:17])[C:3]1=[O:18]
Reactant: CC(=Cc1ccc2c(c1)n(C)c(=O)n2C)[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(=O)Cc1ccc2c(c1)n(C)c(=O)n2C
Temperature: 75 °C
Reaction time: 2.5 h

Procedure:
1,3-Dimethyl-5-(2-nitro-propenyl)-1,3-dihydro-benzoimidazol-2-one (2.23 g) was dissolved in methanol (15 mL) and water (40 mL) and treated sequentially with iron (1.67 g) and iron trichloride hexahydrate (174.3 mg). After heating to 75° C. concentrated hydrochloric acid (8 mL) was added in portions over 0.5 hours. The mixture was stirred at 75° C. for 2.5 hours, cooled, treated with saturated sodium bicarbonate and extracted into ethyl acetate The organic layer was dried over sodium sulfate, and concentrated to give 1,3-Dimethyl-5-(2-oxo-propyl)-1,3-dihydro-benzoimidazol-2-one (1.465 g).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[N:23]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Cc1ccnc(N)n1
Agent: [I-]
Product: Cc1ccnc(N=C2SC[C@@H]3Cc4ccccc4CN23)n1
Yield: 20.2 %

Procedure:
By following the procedure of Example 2, but using (S)-3-methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (18.2 g) and 2-amino-4-methylpyrimidine (8.0 g) as the starting materials, (S)-3-[(4-methylpyrimidin-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (3.0 g) is obtained in the form of white crystals, m.p.=179° C.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[CH2:10][CH2:9][NH:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]([C:30](N)=[O:31])[C:27](N)=[O:28])=[C:21]([CH3:33])[CH:20]=1>C1(C)C(C)=CC=CC=1.ClCCl>[Cl:18][C:19]1[CH:20]=[C:21]([CH3:33])[C:22]([CH:26]2[C:30](=[O:31])[N:7]3[CH2:6][CH2:5][N:4]([O:3][CH3:2])[CH2:10][CH2:9][N:8]3[C:27]2=[O:28])=[C:23]([CH3:25])[CH:24]=1
Reactant: CON1CCNNCC1
Reactant: Cc1cc(Cl)cc(C)c1C(C(N)=O)C(N)=O
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON1CCN2C(=O)C(c3c(C)cc(Cl)cc3C)C(=O)N2CC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A degassed suspension of 5-methoxy-[1,2,5]triazepane hydrochloride salt (100 mg, 0.49 mmol) and triethylamine (0.33 ml, 207 mg, 2.05 mmol) in xylene (2.5 ml) was stirred under argon at 60° C. for 30 minutes in a microwave vial. After further addition of 2-(4-chloro-2,6-dimethyl-phenyl)-malonamide (120 mg, 0.50 mmol), the vial was capped and irradiated twice with microwaves at 180° C. for 10 minutes. The solid deposit on the vial wall was dissolved in dichloromethane, the solvent evaporated, the oily residue dissolved in 5N aqueous sodium hydroxide, the aqueous layer extracted with ethyl acetate (3×) and the combined organic layers discarded. The aqueous alkaline phase was acidified with cooling to pH 2-3 by addition of a 4N HCl solution and the product thoroughly extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Yield: 10 mg of 8-(4-chloro-2,6-dimethyl-phenyl)-3-methoxy-tetrahydro-pyrazolo[1,2-a][1,2,5]triazepine-7,9-dione (compound P2.2) as a beige solid.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=2)[CH:10]([CH2:20][Cl:21])[CH2:9]1)=[O:7])(C)(C)C.C([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1)=[O:35])[CH:28]=2)(O)=O>>[Cl:21][CH2:20][CH:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[N:8]([C:6]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([NH:36][CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:35])[CH:28]=3)=[O:7])[CH2:9]1
Reactant: O=C(NCCN1CCOCC1)c1ccc2cc(C(=O)O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2ccc([N+](=O)[O-])cc21
Product: O=C(NCCN1CCOCC1)c1ccc2cc(C(=O)N3CC(CCl)c4ccc([N+](=O)[O-])cc43)[nH]c2c1
Yield: 50 %

Procedure:
1-(t-Butoxycarbonyl)-3-(chloromethyl)-6-nitroindoline was coupled with 2-carboxy-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide by the method described above and triturated with hot MeOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide as a yellow solid (50%), mp 227-228° C. (dec.). 1H NMR [(CD3)2SO] δ12.15 (s, 1H, indole NH), 8.98 (d, J=2.0 Hz, 1H, H-7), 8.41 (t, J=5.5 Hz, 1H, amide NH), 8.04 (dd, J=8.3, 2.2 Hz, 1H, H-5), 8.01 (s, 1 H, H-3' or H-7'), 7.76 (d, J=8.2 Hz, 1H, H-4 or H-4'), 7.74 (d, J=8.0 Hz, 1H, H-4 or H-4'), 7.57 (dd, J=8.5, 1.1 Hz, 1H, H-5'), 7.28 (d, J=1.4 Hz, 1H, H-3' or H-7'), 4.86 (t, J=10.1 Hz, 1H, H-2), 4.51 (dd, J=10.7, 5.2 Hz, 1H, H-2), 4.19-4.06 (m, 3H, H-3 and CH2Cl), 3.59 (t, J=4.5 Hz, 4H, CH2O), 3.42 (q, J=6.5 Hz, 2H, CONHCH2), 2.50 (t, J=6.9 Hz, 2H, CONHCH2CH2), 2.46-2.41 (m, 4H, NCH2CH2O); 13C NMR δ166.7 (CONH), 160.4 (CON), 147.6, 144.6, 144.0, 135.7, 131.8, 130.8, 129.0 (C-6,8,9,2',6',8',9'), 125.5, 121.6, 119.5, 118.9, 112.0, 111.2, 106.1 (C-4,5,7,3',4',5',7'), 66.2 (CH2O), 57.4 (CONHCH2CH2), 54.0 (C-2), 53.3 (NCH2CH2O), 47.0 (CH2Cl), 42.0 (C-3), 36.6 (CONHCH2). A sample was converted to the hydrochloride salt and triturated with hot EtOH to give 2-[[3-(chloromethyl)-6-nitroindolin-1-yl]carbonyl]-N-[2-(4-morpholinyl)ethyl]indole-6-carboxamide hydrochloride as a pale yellow powder, mp 280-285° C. (dec.). Anal. (C25H26ClN5O5.HCl.H2O) C,H,N.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].P([O-])([O-])([O-])=[O:10]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:10]
Reactant: O=P([O-])([O-])[O-]
Reactant: O=C(O)/C=C/C(=O)O
Product: O=C(O)C[C@H](O)C(=O)O
Temperature: 20 °C
Reaction time: 11 h
Yield: 76 %

Procedure:
These 2 ml were added to 100 ml of phosphate buffer, pH of 7.0, containing 0.05 mole of fumaric acid (neutralized by sodium hydroxide). The reaction mixture was stirred at 20°C. After 11 hours, 1.39 g of fumaric acid remained and 5.05 g of L-malic acid were formed corresponding to a 76% yield.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:7]=2[NH:6][C:5]1=[O:21])=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].O1CCCC1.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:14][C:7]=2[N:6]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:5]1=[O:21])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CBr
Reactant: [N-]=[N+]=NC1CCc2ccc(-c3ccccc3)cc2NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccc(-c3ccccc3)cc21
Reaction time: 2 h
Yield: 81.3 %

Procedure:
While stirring 30 ml of a mixture of 0.75 g (2.70 mmol) of 3-azido-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one obtained in the Synthesis Example A-6, 0.093 g (0.288 mmol) of tetran- butylammonium bromide, 0.17 g (3.03 mmol) of powdery potassium carbonate and tetrahydrofuran at room temperature, 0.35 ml (3.16 mmol) of ethyl bromoacetate was added thereto, followed by stirring for 2 hours. After adding ethyl acetate to the reaction mixture, the obtained mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography. After eluting with hexane:ethyl acetate in a ratio of 15:1 (v/v), 0.8 g of the title compound was obtained as a pale yellow, oily product. Yield 81%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH:56]1[CH2:61][CH2:60][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]C2)[CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:56]1[CH2:57][CH2:58][CH:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:60][CH2:61]1)=[O:5]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: C1CCN(CCOC2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OCCN2CCCC2)CC1
Reaction time: 2 h
Yield: 89.5 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.20 g, 0.67 mmol) and HBTU (0.381 g, 1.01 mmol) were added to DMF (4 mL), to this was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.01 mmol) and then 4-(2-(pyrrolidin-1-yl)ethoxy)piperidine (109) (0.133 g, 0.67 mmol). The reaction was stirred for 2 hours before being evaporated to dryness and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (0.287 g, 89% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.65-1.81 (6H, m), 1.87-1.96 (3H, m), 2.53-2.61 (3H, m), 2.65-2.72 (2H, m), 3.04-3.14 (1H, m), 3.38-3.57 (3H, m), 3.61 (2H, t), 3.97-4.06 (1H, m), 4.28 (2H, s), 7.01 (1H, t), 7.21-7.33 (2H, m), 7.68-7.80 (3H, m), 8.43-8.48 (1H, m), 9.85-9.95 (1H, m); m/z (LC-MS, ESI+), RT=1.88 (M+H 479.5).