Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1.C[Si](Cl)(C)C.[CH3:45][S:46]([OH:49])(=[O:48])=[O:47].[OH-].[Na+]>CN1CCCC1=O.C(Cl)Cl>[CH3:37][N:29]([CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:23]([NH:22][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=2)=[CH:24][CH:25]=1.[CH3:45][S:46]([OH:49])(=[O:48])=[O:47]
Reactant: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Reactant: CN1CCC(N(C)C(=O)c2ccc(N)cc2)CC1
Agent: CS(=O)(=O)O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN1CCC(N(C)C(=O)c2ccc(Nc3ncc(C(F)(F)F)c(Oc4ccc([N+](=O)[O-])cc4)n3)cc2)CC1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
Alternatively, 1.0 g of 2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine is dissolved in 5 mL of 1-methyl-2-pyrrolidinone (NMP). 1.44 g of the mono-4-toluenesulfonic acid salt of 4-amino-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide, 76 μL of trimethylsilylchloride (as water scavenger) and 60 mg methanesulfonic acid are added. The suspension is stirred for 18 hours at 55° C. 15 mL methylenechloride and 10 mL 2N sodium hydroxide solution are added. The organic phase is separated and the solvent is reduced so that 5 g of a concentrated solution remain. To this solution 20 mL 2-propanol and 0.32 g methanesulfonic acid are added. Crystallization occurs. The suspension is filtered, washed and dried to obtain 1.5 g (77% of theory) of product N-methyl-N-(1-methyl-piperidin-4-yl)-4-[4-(4-nitro-phenoxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-benzamide as methanesulfonic acid salt.
Reaction SMILES: C(ON=O)CC(C)C.I[CH2:10][I:11].[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:16]([CH2:27][CH3:28])=[N:15][C:14]=1C#N>C(Cl)(Cl)Cl>[C:13]([C:14]1[N:15]=[C:16]([CH2:27][CH3:28])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[C:10]=1[I:11])#[N:12]
Reactant: ICI
Reactant: CCc1nc(C#N)c(N)n1CCCCNS(C)(=O)=O
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CCc1nc(C#N)c(I)n1CCCCNS(C)(=O)=O
Temperature: 80 °C
Yield: 57 %

Procedure:
A solution of isoamylnitrite (0.30 g, 2.6 mmol), diiodomethane (2 mL), and chloroform (3 mL) was heated at 85° C. A mixture of N-[4-(5-amino-4-cyano-2-ethyl-1H-imidazol-1-yl)butyl]methanesulfonamide (0.2 g, 0.7 mmol) and chloroform (8 mL) was added over a period of 15 minutes. The reaction was stirred and heated at 80° C. for an additional 10 minutes, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was purified through a layer of silica gel (15 g, eluting sequentially with chloroform, 2% methanol in chloroform, 4% methanol in chloroform, 8% methanol in chloroform, and 10% methanol in chloroform) to provide 0.16 g (57%) of N-[4-(4-cyano-2-ethyl-5-iodo-1H-imidazol-1-yl)butyl]methanesulfonamide as an amber syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O>S(=O)(=O)(O)O>[Cl:8][C:6]1[CH:5]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=1)[S:9][CH2:10][CH2:11][C:12]2=[O:14]
Reactant: O=C(O)CCSc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C1CCSc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A deep red colour was immediately observed when 3-(2,4-dichlorophenylthio)propanoic acid (1.20 g, 4.78 mmol; from step (ii) above) was added to conc. sulfuric acid (30 mL). After stirring overnight at ambient temperature the reaction mixture was poured into ice. The red colour disappeared. Extraction with diethyl ether, washing with aq., sat. sodium hydrogencarbonate, drying (MgSO4) and removal of the solvent in vacuo afforded a deep yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[OH-].[Na+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:6][CH3:7])=[CH:8][CH:9]=1
Reactant: CNc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1ccc(Br)cc1N
Temperature: 70 °C

Procedure:
A suspension of 4-bromo-N-methyl-2-nitroaniline (5328 mg, 22.04 mmol) in EtOH (100 ml) was treated with SnCl2-2H2O (25.61 g, 110.2 mmol) and the resulting mixture heated at 70° C. under an atmosphere of Nitrogen for 5 h. The reaction mixture was then cooled to rt and treated with ice-water (50 ml) followed by aqueous NaOH (4 N) until pH>8. This basic mixture was then extracted with EtOAc (3×150 ml) and the combined extracts washed with brine (3×100 ml), dried over MgSO4 and concentrated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=2.68 (s, 3 H), 4.74 (brs, 3 H), 6.27 (d, 1 H, J=8.4 Hz), 6.61 (dd, 1 H, J=2.0 & 8.4 Hz) and 6.66 (d, 1 H, J=2.0 Hz). MS(ES+): m/z 201.10 and 203.12[MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.C(#N)C.[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.O>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:28]1[N:29]=[N:30][CH:31]=[N:27]1
Reactant: c1nnn[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OCCCCCCn2ncnn2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Stir overnight at room temperature 300 mg. of the iodide prepared in Examples 2 and 3, 3 ml. acetonitrile, 63 mg. 1-H-tetrazole and 274 mg. cesium carbonate in a reaction flask. Add an additional. 189 mg. 1-H-tetrazole and 100 mg. cesium carbonate, let stir one week at room temperature. Work up the reaction mixture in methylene chloride with a water wash. Elute on a coarse silica column with methylene chloride then ethyl acetate/methylene chloride. Isolate two fractions of the title compound, the less polar fraction and the more polar fraction. One of the fractions is the 1-substituted tetrazole and the other fraction is the 2-substituted tetrazole.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][CH2:21][C:22]([O:24]C)=O)[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]>CO.C(OCC)(=O)C>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([S:19][CH2:20][CH2:21][C:22]([NH:2][NH2:3])=[O:24])[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])([CH3:7])[CH3:6]
Reactant: NN
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NN)cc(C(C)(C)C)c1O
Yield: 68.5 %

Procedure:
Hydrazine monohydrate (16 mL, 324 mmol) is added to a room temperature solution of methyl 3-[[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate (3.5 g, 10.8 mMol) in methanol (110 mL). The reaction mixture is heated at reflux for 2 hours, then cooled, diluted with ethyl acetate and washed six times with water and once with brine. Drying the organic phase over magnesium sulfate and evaporation provides a crude solid which is chromatographed on a column of silica with methanol/chloroform (5/95) to afford 2.4 g (64%) of 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoic acid hydrazide, mp 107.0°-110.0° C.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][C:15]([OH:17])=[O:16])=[CH:5][N:6]=[CH:7]2>[OH-].[Na+]>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[N:6][CH:5]=[C:4]2[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc2cncc(CC(=O)O)c2c1Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2cncc(CC(=O)O)c2c1
Reaction time: 20 h

Procedure:
N-Chlorosuccinimide (0.347 g, 2.60 mmol) is added to a solution of 6-methoxyisoquinoline (Synth. Commun. 1999, 29, 1617) (0.207 g, 1.30 mmol) in acetic acid (9 ml). The reaction is heated at 50° C. for 3 hours, cooled to ambient temperature, evaporated and partitioned between ethyl acetate and 1M aqueous sodium hydroxide. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated afford 5-chloro-6-methoxyisoquinoline, [MH]+ 194. A solution of this intermediate (0.175 g, 0.90 mmol) in THF (4.5 ml) and acetic anhydride (0.101 ml, 1.08 mmol) is treated with sodium triacetoxyborohydride (0.229 g, 1.08 mmol) and the reaction is stirred at ambient temperature for 22 hours. The solvent is evaporated, the residue is taken into ethyl acetate, washed with 0.5 M aqueous hydrochloric acid, then brine and dried over magnesium sulfate. Evaporation affords 1-(5-chloro-6-methoxy-1H-isoquinolin-2-yl)-ethanone, mp 78-80° C. A suspension of this intermediate (0.150 g, 0.60 mmol) and glyoxylic acid (76 mg, 0.80 mmol) in 6M aqueous hydrochloric acid (2.8 ml) is heated at 100° C. for 3 hours. After cooling to ambient temperature, the resultant solid is, collected by filtration to afford (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid, [MH]+ 252. A suspension of this intermediate (0.970 g, 3.38 mmol) and ammonium formate (1.05 g, 16.9 mmol) in 1:1 acetic acid-water (25 ml) is treated with 10% Pd/C (0.730 g) and stirred at ambient temperature for 16 hours. After filtration through Celite®, the combined filtrate and washings are evaporated and purified by Soxhilet extraction with acetone to afford (6-methoxy-isoquinolin-4-yl)-acetic acid [MH]+ 218. Alternatively reduction of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid to afford (6-methoxy-isoquinolin-4-yl)-acetic acid is accomplished by stirring a suspension of (5-chloro-6-methoxy-isoquinolin-4-yl)-acetic acid (20 g, 69.4 mmol) in 1 Molar sodium hydroxide solution (400 mL) for 20 min, filtering off the resultant salt and then treating with hydgrogen gas in the presence of 10% Pd/C (1.4 g) at atmospheric pressure for 2.25 h. The resulting suspension is filtered through glass wool and celite, washing with water (50 mL). The solution is then cooled in an ice water bath and slowly (30 min) neutralised and then acidified with 5 Molar hydrochloric acid (80 ml). A suspension forms and further crystalisation is encouraged by standing at 5° C. for 20 h. The resulting crystals are removed by filtration and washed with ice cold ethanol (25 ml) drying under reduced pressure gives (6-methoxy-isoquinolin-4-yl)-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19](O)=[O:20])[CH2:11][CH2:10]2.C(N1C=CN=C1)([N:27]1C=CN=C1)=O.C([O-])(=O)C.[NH4+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH2:18][C:19]([NH2:27])=[O:20])[CH2:11][CH2:10]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CN1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of [6-(3-fluoro-benzyloxy)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid (0.245 mg, 0.744 mmol) and 1,1′-carbonyl-diimidazole (0.229 mg, 1.41 mmol) in N,N′-dimethylformamide (6 mL) was stirred at room temperature for 0.5 h. Ammonium acetate (0.917 g, 11 mol) was added and the mixture was stirred 2 h. Water was added and the mixture was extracted with ethyl acetate. Drying and evaporation of the solvent left a solid which was recrystallised with ethyl acetate and ether. MS: m/e=329.3 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]1[C:42](=[O:43])[NH:41][C:39](=[O:40])[CH2:38]1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[C:42](=[O:43])[CH2:37][CH2:38][C:39]2=[O:40])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1CCCN1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-benzylpiperazin-1-yl)propan-1-ol (48.5 g/0.21 mol), triphenylphosphine (81.6 g/0.31 mol), succimide (30.7 g/0.31 mol) in tetrahydrofuran (1000 ml) was added dropwise diethylazodicarboxylate (49.0 ml/0.31 mol) and the mixture was stand overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (Si/230-400 mesh/dichloromethane:methanol=15:1) to give a colorless oil (55.1 g/83%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=5)[C:27]#[N:28])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:35][CH2:34]1.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]>[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]5[C:19]6=[N:20][C:21]([C:24]7[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=7)[C:27]#[N:28])=[CH:22][N:23]=[C:18]6[N:17]=[N:16]5)[CH2:9]4)=[N:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:35][CH2:34]1
Reactant: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: N#Cc1cccc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(Cc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cccc(C#N)c7)nc65)C4)nc3)cc2)CC1
Temperature: 80 °C
Yield: 32.7 %

Procedure:
(S)-3-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile (30 mg, 0.063 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzyl)piperazine (24 mg, 0.094 mmol), Pd(dppf)2Cl2 (2 mg, 0.003 mmol), and Cs2CO3(62 mg, 0.18 mmol) were dissolved in dioxane (4 ml)+H2O (1 ml), and then degassed with N2 (gas), followed by stirring at 80° C. for hours. After the completion of the reaction, the reaction mixture was extracted with H2O, EA, and brine, followed by drying (Na2SO4), filtration, and concentration under reduced pressure, and the residue was purified by column chromatography (MeOH:MC=1:10), to give (S)-3-(1-((4-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile (12.1 mg, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:24]>>[C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:22]=[CH:21][C:12]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:28][CH:27]=1)#[N:24]
Reactant: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Reactant: N#CCc1ccc(B(O)O)cc1
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(CC#N)cc3)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 212 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-(3-methoxypropyl)nicotinamide and (4-(cyanomethyl)phenyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (quin, J=6.7 Hz, 2 H) 3.18 (s, 3 H) 3.21-3.30 (m, 2 H) 3.33 (t, J=6.2 Hz, 2 H) 3.94 (s, 2 H) 7.25 (d, J=8.3 Hz, 2 H) 7.86 (d, J=8.1 Hz, 2 H) 8.25-8.34 (m, 2 H) 8.36 (br. s., 1 H) 8.62 (t, J=5.6 Hz, 1 H) 8.79-8.86 (m, 1 H) 12.97 (br. s., 1 H). MS m/z 392 [M+H]+.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:38]=[C:39]=[O:40])[CH2:35][CH2:36][CH3:37]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:39]([NH:38][CH2:34][CH2:35][CH2:36][CH3:37])=[O:40])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: CCCCN=C=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.6 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min n-butyl isocyanate (0.27 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (70 mL). The CH2Cl2 solution was washed with 1N HCl (30 mL), H2O (30 mL), brine (30 mL) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by chromatography (SiO2, CH2Cl2: EtOAc 1:1) to give N-{[2-(2,6-dioxo(3-piperidyl))1,3-dioxoisoindolin-4-yl]methyl}(butylamino)carboxamide (0.44 g, 61%) as a white solid: mp 172-174° C.; 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 7.86-7.68 (m, 3H), 6.42 (t, J=5.9 Hz, 1H), 6.12 (t, J=5.4 Hz, 1H), 5.18-5.11 (dd, J=5.2 and 12.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 1H), 3.03-2.83 (m, 3H), 2.64-2.51 (m, 2H), 2.08-2.04 (m, 1H), 1.37-1.22 (m, 4H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 172.70, 169.77, 167.54, 167.00, 157.98, 141.14, 134.56, 133.33, 131.47, 126.94, 121.58, 48.80, 38.98, 38.70, 32.01, 30.90, 21.95, 19.46, 13.64; Anal. Calcd. For C19H22N4O5: C, 59.06; H, 5.74; N, 14.50. Found: C, 59.24; H, 5.53; N, 14.37.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][NH2:6].[Cl:8][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[CH:19]=[N:18][CH:17]=[C:16]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:15]=3[C:14](=O)[C:13]=2[C:12](F)=[CH:11][CH:10]=1>N1C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:6]=[C:14]3[C:15]4[C:16]([O:24][CH2:25][C:26]5[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=5)=[CH:17][N:18]=[CH:19][C:20]=4[C:21](=[O:23])[C:22]=1[C:13]=23
Reactant: CN(C)CCNN
Reactant: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2-c2nn(CCN(C)C)c4ccc(Cl)c(c24)C3=O)cc1
Reaction time: 2 h

Procedure:
A solution of N-[2-(dimethylamino)ethyl]hydrazine (8.5 mg) in pyridine (0.5 mL) is added to 9-chloro-6-fluoro-4-(p-methoxybenzyloxy) benzo[g]isoquinoline-5,10-dione of Preparative Example 29 (13 mg) over a period of 2 minutes at 0° C. under a nitrogen blanket and the mixture is stirred for 2 h. The excess pyridine and some excess hydrazine are removed under a nitrogen stream. The residue is placed under vacuum overnight. The product is purified by thick layer chromathography (silica gel, 10 cm by 20 cm) using 4% methanol/96% dicloromethane. The major yellow band is scraped from the plate and the yellow compound extracted into 25% methanol/75% dicloromethane. Removal of the solvent gives 5-chloro-2-[2-(dimethylamino)ethyl]-10-(p-methoxybenzyloxy) isoquino[5,6,7-cd]indazole-6(2H)-one (3 mg) as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:6][CH:7]=1.[C:29]([CH2:33][C:34](OC)=[O:35])(=O)[CH2:30][CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Si:12]([O:11][CH2:10][CH2:9][O:8][C:5]1[N:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:29]([CH2:30][CH3:31])=[CH:33][C:34]2=[O:35])([C:25]([CH3:28])([CH3:27])[CH3:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: CC(C)(C)[Si](OCCOc1ccc(N)cn1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCc1cc(=O)c2nc(OCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2[nH]1
Yield: 62 %

Procedure:
A solution of compound C (10 g), methyl propionylacetate (11.5 g) and p-toluenesulphonic acid (0.1 g) in benzene (40 ml) was heated under reflux with azeotropic removal of water for 20 hours. Volatile material was removed by evaporation and the residue added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (30 ml). The solution was heated under reflux for 1 hour, cooled and diluted with hexane (100 ml). The precipitated solid was filtered off and triturated with hot methanol (100 ml) to give 2-ethyl-6-[2-(trimethylsilyl)ethoxy]-1,5-naphthyridin-4-(1H)-one (D) (in 62% yield) as a white solid, m.p. 193° C.; NMR: -0.1(s,9H), 0.85(t,2H), 1.3(t,3H), 2.8(q,2H), 4.1(t,2H), 6.55(s,1H), 6.9(d,1H), 8.2(d,1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C@H](C3C=CC=CC=3)C)[CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][C:33]([N:14]1[CH2:15][CH2:16][C@@H:12]([C:9]2([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:10]2)[CH2:13]1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1([C@@H]2CCN(C(=O)OCc3ccccc3)C2)CC1
Yield: 75.4 %

Procedure:
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine (1.70 g, 5.15 mmol) was dissolved in dichloromethane (34 ml), and benzylchloroformate (1.10 ml, 7.73 mmol) was added dropwise while stirring and cooling with ice. The reaction solution was then stirred at room temperature for 2.5 hours and then stirred at 40° C. for 1.5 hours. After letting the reaction solution cool, the reaction solution was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 1.40 g (75%) of the title compound was obtained in the form of a colorless syrup from an n-hexane:ethyl acetate=2:1 eluate. The instrumental analysis data for this resulting compound agreed with the data indicated in PCT/JP96/00208.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:44])[CH2:7][CH2:8][NH:9][C:10](=[O:43])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][CH:33]=2)=[O:30])[CH:18]2[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[CH:13][CH:12]=1)C.CCO.[Li]>O>[O:22]1[C:21]2([CH2:26][CH2:27][CH:18]([CH:17]([NH:28][C:29]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][C:39]([F:41])([F:40])[F:42])=[CH:36][CH:37]=3)=[O:30])[C:14]3[CH:15]=[CH:16][C:11]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:43])=[CH:12][CH:13]=3)[CH2:19][CH2:20]2)[O:25][CH2:24][CH2:23]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCC3(CC2)OCCO3)cc1
Agent: [Li+]
Agent: [Li]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCNC(=O)c1ccc(C(NC(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCC3(CC2)OCCO3)cc1

Procedure:
180 mg LiOH dissolved in 2.2 mL H2O was added to the entire yield of the above 3-{4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-trifluoromethoxyphenyl)ureidomethyl]benzoylamino}propionic acid ethyl ester dissolved in 22 mL abs. EtOH. After 1 hour at 25° C. the solvent was evaporated and 10 mL H2O followed by 500 mg citric acid dissolved in 20 mL H2O was added to the residue affording a pH of 4-5. The resulting product was a mixture of the acid and its lithium salt.