Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25](O)=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:10]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:49]2[N:50]=[CH:51]C=CC=2N=N1.C(NC(C)C)(C)C.CNC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[C:22]([CH2:24][C:25]([N:50]([CH3:51])[CH3:49])=[O:26])[CH:21]=[N:20][CH:19]=3)[CH:16]=2)[N:11]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)O)n3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cncc(CC(=O)N(C)C)n3)cc12
Temperature: 60 °C
Yield: 102.4 %

Procedure:
Crude {6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrazin-2-yl}-acetic acid (0.55 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (251 mg, 0.66 mmol), and di-iso-propylamine (114.9 μL, 0.66 mmol) were dissolved in tetrahydrofuran (5 mL) and 2 M dimethylamine (412 μL, 0.825 mmol) was added. The mixture was heated to 60° C. in a capped vial for 30 minutes, cooled, diluted with ethyl acetate and washed with saturated sodium bicarbonate (1×), saturated ammonium chloride (1×) and brine (1×). The organics were dried over sodium sulfate, filtered and concentrated to yield a yellow foam (305 mg, >100%). The crude material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>>[C:21]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: CCCC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(3-methylbenzoyl)indole (Example 21) and butyryl chloride. m.p.: 127-130° C. 1H-NMR (CDCl3) δ: 10.03 (1H, br s), 8.35-8.20 (2H, m), 7.62-7.54 (2H, m), 7.48-7.40 (2H, m), 7.28 (1H, d, J=1.8 Hz), 7.08 (1H, dd, J=1.8, 9.2 Hz), 2.55-2.35 (5H, m), 1.90-1.72 (2H, m), 1.04 (3H, t, J=7.3 Hz)
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:14][C:15]1[C:23]2[C:19](=[N:20][S:21][N:22]=2)[CH:18]=[CH:17][C:16]=1[NH2:24]>CC(C)=O.CO>[C:5]([NH:3][C:2]([NH:24][C:16]1[CH:17]=[CH:18][C:19]2=[N:20][S:21][N:22]=[C:23]2[C:15]=1[Cl:14])=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc2nsnc2c1Cl
Reactant: O=C(Cl)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(NC(=S)Nc1ccc2nsnc2c1Cl)c1ccccc1
Reaction time: 0.17 h

Procedure:
The starting material is obtained as follows: A solution of 6 g ammonium thiocyanate in 200 ml acetone is treated with 7 ml benzoyl chloride and stirred for 10 minutes. To this solution 6 g of 4-chloro-5-amino-2,1,3-benzothiadiazole in 200 ml of methanol is added. The mixture is boiled for 2 hours and cooled yielding N-benzoyl-N'-(4-chloro-2,1,3-benzothiadiazol-5-yl)thiourea (M.Pt. 220°-222° from methanol). The precipitate was filtered off and quickly heated to reflux with 100 ml of a 2 N aqueous solution of sodium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11])[C:5]#[N:6].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:28][N:27]=[N:26][N:6]=2)[CH:7]=[CH:8][C:9]=1[C:10]([N:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][N:15]2[CH:23]=[CH:24][CH:25]=[C:14]2[CH2:13]1)=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nnn[nH]2)cc1Cl)N1Cc2cccn2Cc2ccccc21
Temperature: 100 °C

Procedure:
To a solution of 3-chloro-4-(5H,11H-pyrrolo[2,1-c][1,4]-benzodiazepine-10-carbonyl)-benzonitrile (0.348 g) in dimethylformamide (2 ml) was added sodium azide (0.078 g) and ammonium chloride (0.065 g). The mixture was heated to 100° C. for 18 hours.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl>C(O)CCC.O1CCOCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][NH:28]4)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[C:21]=1[CH3:22]
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 69.9 %

Procedure:
A mixture of (S)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (330 mg, 1.23 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (351 mg, 1.47 mmol) and DIPEA (320 μL, 2.45 mmol) in n-butanol (6 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). A solution of the compound thus obtained in MeOH (5 mL) and 4N HCl in dioxane (1 ml) was stirred at RT for 1 h then the volatiles were removed under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated solution of NaHCO3. A white solid precipitated and was collected by filtration to afford 183 (333 mg, 70%). LCMS (Method K): RT 3.46 min [M+H]+ 388.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.55 (1H, s), 8.06-8.00 (2H, m), 7.71-7.39 (7H, m), 7.05 (1H, dd, J=10.58, 8.77 Hz), 5.30 (1H, br s), 1.70 (3H, d, J=1.84 Hz), 1.53 (3H, d, J=6.84 Hz)
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C(OC([NH:18][CH2:19][C@@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@H:25]2[C@@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2)=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:18][CH2:19][C@@:20]1([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][C@H:25]2[C@@H:21]1[CH:22]=[C:23]([CH3:27])[CH2:24]2
Reactant: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CNC(=O)OC(C)(C)C)CC(=O)O
Agent: O=S(=O)(O)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C[C@H]2[C@@H](C1)C[C@@]2(CN)CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.5 %

Procedure:
[(1S,5R,6R)-6-tert-butoxycarbonylaminomethyl-3-methylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonic acid (5.8 g, 16.4 mmol) was suspended in methylene chloride (50 mL). To the suspension, triethylamine (4.6 ml, 32.7 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The resulting solid was collected by filtration and washed with isopropanol to obtain the compound of interest as a white solid (2.0 g, 63%).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:36])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:6]([CH3:36])=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][C:8]=3[CH3:10])=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[CH:27]3)=[N:22]2)=[CH:34][CH:33]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless foam. MS: m/e=503.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])([O-:21])=[O:20]>C1COCC1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])[C:24]4[CH:28]=[CH:29][CH:30]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(N)cc3CC[C@@H]12
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Reaction time: 4 h

Procedure:
A 620 mg portion of (4aR)-(10bR)-4,10b-dimethyl-8-amino-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was dissolved in 100 ml of THF, and an equivalent amount of 3-nitrobenzoyl chloride (500 mg) was added. The reaction mixture was stirred for 4 h, and was then evaporated to dryness under vacuum. The residue was purified by chromatography on silica gel, eluting with 10% methanol in ethyl acetate, and the product-containing fractions were evaporated and the resulting solid was crystallized from dichloromethane/hexane to obtain 595 mg of the desired product, m.p. 240°-242°. FDMS: m/e=393. α[D]589
Reaction SMILES: ClCC(=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].[C:29]([C:32]#N)([CH3:31])=[O:30]>>[C:11]1([CH2:10][N:17]2[CH2:22][CH2:21][N:20]([CH:32]([C:29](=[O:30])[CH3:31])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C#N
Reactant: CCOC(=O)C(=O)CCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C(C)=O)N1CCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A mixture of ethyl 3-chloro-2-oxopropionate (85.15 g, 0.52 mol), N-benzylpiperazine (6.42 g, 0.49 mol) and K2CO3 (7.1 g, 0.52 mol) in 1L of AcCN was stirred at 50° C. for 24 h. AcCN was removed in vacuo. The residue was partitioned between aqueous Na2CO3 solution (5%, 300 mL) and EtOAC (300 mL×2). The combined EtOAc solution was extracted with 1N aqueous HCl solution. The aqueous solution was separated, neutralized with Na2CO3 to pH 9 and extracted with EtOAc (250 mL×2). The EtOAc layer was separated, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to give 132.60 g (89%) of the desired product as pale yellow liquid. IR(KBr): 3011, 2940, 2810, 1740, 1720, 1650, 1358, 1325, 1250, 1016 cm-1 ; 1H-NMR (80 MHz, CDCl3): δ 1.17-1.24 (t, J=7.1 Hz, 3H, CH3CH2OCO--), 2.05 (s, 3H, CH3CO--), 2.40-2.50 (m, 4H, piperazinyl-H), 2.60-2.70 (m, 4H, piperazinyl-H), 3.45 (s, 2H, --CH2 --Ph), 3.84 (s, 1H, CH3CO--CH--), 4.11-4.18 (q, J=7.1 Hz, 2H, CH3CH2OCO--), 7.10-7.29 (m, 5H, Ph-H) ppm; EI MS m/z (relative-intensity): 304 (M+, 13), 261 (100), 231 (10), 170 (29), 91 (95).
Reaction SMILES: [ClH:1].N[C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3.N([O-])=O.[Na+]>O>[Cl:1][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH:9]([CH3:20])[N:10]3[C:15]=2[C:14]=1[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11]3
Reactant: Cl
Reactant: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1CCc2ccc(Cl)c3c(=O)c(C(=O)O)cn1c23
Reaction time: 1 h

Procedure:
A mixture of 75 ml. of 6N hydrochloric acid and 10-amino-6,7-dihydro-5-methyl-1-oxo-benzo[ij]quinolizine-2-carboxylic acid (12.9 g., 0.05 mole) is diazotized at 5° to 10° C. with sodium nitrite (4.14 g., 0.06 mole) dissolved in about 10 ml. of water. The cold mixture is filtered, then it is added to a mixture of cuprous chloride (19.7 g., 0.1 mole) and concentrated hydrochloric acid (150 ml.) while maintaining the temperature below 20° C. After stirring one hour the mixture is diluted with water to provide a creamy-white solid which is collected by filtration. Two recrystallizations from N,N-dimethyl formamide provide 10-chloro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 219.5°-222° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(C(C)C)CC)(C)C.C([N:48]1[CH:52]=[C:51]([CH2:53][C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)[N:50]=[CH:49]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:77]CCl>>[ClH:77].[F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:50]3[C:51]([CH2:53][C:54]4[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=4)=[CH:52][N:48]=[CH:49]3)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2cccc(OC(F)(F)F)c2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cl
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3cccc(OC(F)(F)F)c3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-trifluoromethoxyphenyl)-5-hydroxymethylpyridine (66 mg, 0.25 mmol), diisopropylethylamine (0.085 mL, 0.49 mmol), and 1-trityl-4-(4-cyanobenzyl)imidazole (105 mg, 0.25 mmol) in dichloromethane (1.4 mL) at -78° C. was added trifluoromethanesulfonic anhydride (0.041 mL, 0.25 mmol) and the mixture stirred at -78° C. for 1 hour. The reaction was allowed to warm to ambient temperature and stirred for 4 hours. The solvent was evaporated in vacuo. The residue was dissolved in methanol (15 mL), heated at reflux for 1 hour, and the solvent evaporated in vacuo. The residue was partitioned between dichloromethane and sat. aq. Na2CO3 solution. The organic layer was dried, (Na2SO4) and the solvent evaporated in vacuo. The residue was chromatographed (Silica gel, 3% MeOH in CH2Cl2). The amine was converted to the HCl salt by treatment with 1.0M HCl in aqueous acetonitrile. Evaporation of the solvent in vacuo afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: CSc1nnc(-c2ccc(Cl)cc2)c(C)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Yield: 15 %

Procedure:
A solution of 6-(4-chlorophenyl)-5-methyl-3-methylthio-1,2,4-triazine (32.4 g) and hydrazine hydrate (40.8 g) in ethanol (110 ml) was heated for 2 hours. After cooling, the precipitates were collected by filtration, washed with ethanol, dried and recrystallized from ethanol to give 6-(4-chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.54 g).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)#[N:2].C(N(CC)CC)C.[SH2:25]>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][N:15]=[C:14]([CH3:17])[CH:13]=1)=[O:11])[C:4]1[O:8][CH:7]=[CH:6][CH:5]=1)(=[S:25])[NH2:2]
Reactant: S
Reactant: Cc1cc(C(=O)NC(C#N)c2ccco2)sn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)NC(C(N)=S)c2ccco2)sn1
Temperature: 25 °C

Procedure:
1.0 g of N-(alpha-cyanofurfuryl)-3-methylisothiazole- 5-carboxylic acid amide was dissolved in 30 ml of tetrahydrofuran, and 0.6 ml of triethylamine was added. With stirring at room temperature, hydrogen sulfide gas was introduced into the mixture. Five hours later, the reaction solvent was evaporated under reduced pressure. Water was added to the residue. The precipitated crystals were separated by filtration to give 1.1 g of the desired N[-(alpha-thiocarbamoyl)furfuryl]-3-methylisothiazole-5-carboxylic acid amide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:20])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]#N.[OH2:21].Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[C:3]([Br:20])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]=2[C:18]([OH:23])=[O:21]
Reactant: O
Reactant: N#Cc1c2cc(Br)c(N)cc2nn1-c1ccc(F)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1cc2nn(-c3ccc(F)cc3)c(C(=O)O)c2cc1Br
Temperature: 100 °C
Yield: 85 %

Procedure:
A suspension of 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carbonitrile (50 mg, 0.14 mmol) in 10% NaOH (5 mL) was heated at 100° C. for 48 h. The reaction mixture was cooled to RT and poured into water (10 mL). After pH was adjusted to 4 with 1 N HCl, the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated to get 6-amino-5-bromo-2-(4-fluorophenyl)-2H-indazole-3-carboxylic acid (45 mg, yield: 85%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.77˜7.82 (m, 2H), 7.45˜7.52 (m, 2H), 7.03 (s, 1H), 6.61 (s, 1H), 5.60 (s, 2H). MS (M+H)+: 350/352.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:14](=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:13](=[O:29])[C:12]=2[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:30](OC(=O)C)(=[O:32])[CH3:31].[C:37]([O-])(=[O:39])[CH3:38].[K+]>[Zn].C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:27]=[CH:26][C:25]2[C:12](=[C:13]([O:29][C:37](=[O:39])[CH3:38])[C:14]3[C:23]([C:24]=2[O:28][C:30](=[O:32])[CH3:31])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=3)[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCOc1ccc2c(c1)C(=O)c1cc3ccccc3cc1C2=O
Agent: [K+]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc2c(OC(C)=O)c3cc4ccccc4cc3c(OC(C)=O)c2c1

Procedure:
With stirring, 2,0 g (31.05 mmol) of zinc powder are added to a mixture of 4 g (10.35 mmol) of 2-n-octyloxytetracene-5,12-dione obtained in Example 1.1., 40 ml of ethyl acetate, 25 ml of acetic anhydride and 3.05 g (31.05 mmol) of potassium acetate. The mixture is stirred for 40 minutes at 25° C. and then filtered. The residue is washed 4 times with CH2Cl2. The filtrates are connected by evaporation and the residue is recrystallised from CH2Cl2 /pentane, then from toluene. Yield: 4.1 g (84%), m.p. 107°-111° C.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:69][N:70]1[CH2:75][CH2:74][S:73][CH2:72][CH2:71]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:68])[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:68][N:58]([C:52]1[CH:53]=[CH:54][CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:69][N:70]3[CH2:71][CH2:72][S:73][CH2:74][CH2:75]3)[CH2:45][N:46]=1)=[CH:57]2)[S:59]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=1)(=[O:60])=[O:61]
Reactant: CN(c1cccc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.33 h
Yield: 5.3 %

Procedure:
To a solution of triphenylphosphine oxide (0.79 g) in dichloromethane (5 mL) was slowly added trifluoromethanesulfonic anhydride (0.38 mL) under ice-cooling, and the mixture was stirred for 20 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (0.67 g) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=4:6-6:4). The obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (29 mg, yield: 5%) as colorless crystals. MS:488(MH+). melting point 142-144° C.
Reaction SMILES: [Br:1][C:2](=[CH:5][CH3:6])[CH:3]=[O:4].C(N(CC)CC)C.Cl[Si:15]([CH3:18])([CH3:17])[CH3:16].[I-].[Na+]>C(#N)C.C(OCC)C>[Br:1][C:2]([CH:5]=[CH2:6])=[CH:3][O:4][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC=C(Br)C=O
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC#N
Product: C=CC(Br)=CO[Si](C)(C)C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
Furthermore, 2.98 g (20 mmoles) of 2-bromobut-2-enal and 3 g (30 mmoles) of triethylamine are introduced into a 250 ml container. At room temperature, in a nitrogen atmosphere with agitation, there is added 1.63 g (30 mmoles) of chlorotrimethylsilane followed, drop by drop, by the solution of sodium iodide in acetonitrile which was previously prepared. After reaction for 90 minutes, 60 cc of anhydrous petroleum ether (petroleum ether 40-60) are added and agitation is effected for 30 minutes. The precipitate which forms is filtered off under a nitrogen atmosphere and then washed twice with 30 ml of anhydrous petroleum ether. The upper phase of the filtrate (petroleum ether) is collected and the lower phase (acetonitrile) extracted 3 times with, in each case, 30 ml of petroleum ether. The petroleum ether fractions are collected and 5 g of anhydrous magnesium sulfate added thereto. Filtration is effected over fritted glass and the solvent eliminated by vacuum distillation (rotary evaporator) in an inert atmosphere. The residue obtained is diluted in 80 cc of anhydrous ethyl ether; the precipitate is filtered and the solvent evaporated under an atmosphere of nitrogen. 3.76 g of product are obtained, representing a yield of 85%. Purity (GC) of the product obtained is 98% and its structure is confirmed by nuclear magnetic resonance and mass spectrometry.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][N:5]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15].[OH-].[Li+].Cl>C1COCC1.O>[C:20]([O:19][C:17]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[N+:14]([O-:16])=[O:15])[CH2:4][C:3]([OH:24])=[O:2])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)CN(Cc1ccc(F)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of crude [tert-butoxycarbonyl-(4-fluoro-2-nitro-benzyl)-amino]-acetic acid methyl ester (5.91 g, 17.2 mmol) in THF (50 mL) was added lithium hydroxide (4.35 g, 103.6 mmol,) dissolved in water (17 mL). The reaction was stirred at r.t. overnight. After completion of the reaction, as confirmed by TLC, the reaction mixture was acidified to pH 4 using 10% HCl and crude compound was extracted with MeOH and CHCl3 (1:9, 3×50 mL). The combined organic layers were dried over Na2SO4. The solvents were removed in vacuo to afford 2-(tert-butoxycarbonyl(4-fluoro-2-nitrobenzyl)amino)-acetic acid (5.11 g, 90%) as brown thick gel, which was used as such without any further purification for the next step.