Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=O)[CH2:12][CH:13]=O)=[CH:7][CH:6]=1.OO>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N:3]=[N:2][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(C(=O)C(CC=O)c2ccc(Cl)cc2)cc1
Agent: OO
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nnccc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Hydrazine hydrate (0.8 mP, 16.5 mmol) was added to a solution of 3-(4-chlorophenyl)-4-[4-(methylsulfonyl)phenyl]-4-oxo-butyraldehyde (4.5 g, 12.8 mmol) in ethanol (100 ml), followed by stirring at room temperature for 1 hour. Hydrogen peroxide solution 31% (6 ml) was added to the reaction mixture, and the resulting mixture was stirred at 60° C. for 18 hours. The mixture was concentrated under reduced pressure and the residue was separated and purified by chromatography on a silica gel column [silica gel 70 g, chloroform/methanol (50/1)], whereby the title compound was obtained as a pale yellow amorphous solid (2.60 g, 58.8%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH:21]=O)[CH3:18].C([BH3-])#N.[Na+].C(N(CC)CC)C>CO.[Cl-].[Zn+2].[Cl-]>[CH2:17]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH3:16])=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)[CH3:18]
Reactant: CCc1cccc(C)c1C=O
Reactant: CCOC(=O)c1nc2c(N)cccn2c1C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc2c(NCc3c(C)cccc3CC)cccn2c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 8.1 %

Procedure:
To a stirred mixture of ethyl 8-amino-3-methylimidazo[1,2-a]pyridin-2-carboxylate (1.53 g, 7.0 mmol) in methanol (25 ml) were added 2-ethyl-6-methylbenzaldehyde (1.1 g, 7.1 mmol), zinc(II)chloride (1.1 g, 8.0 mmol) in methanol (10 ml) and sodium cyanoborohydride (0.5 g, 8.0 mmol). The reaction mixture was refluxed for 4 h. and then stirred at room temperature for 20 h. Triethylamine (2.5 ml) was added and the mixture was stirred for 30 min. and evaporated under reduced pressure. Purification of the residue by column chromatography twice on silica gel using 1) methylene chloride:methanol (95:5) 2) heptane:isopropyl ether (1:5) as eluent gave 0.2 g (8%) of the title compound.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[C:17]([NH:19][C@@H:20]([C:23]3[CH:28]=[C:27]([CH3:29])[C:26]([Cl:30])=[C:25]([CH3:31])[CH:24]=3)[CH2:21][CH3:22])[CH:16]=[CH:15][C:14]=2[Cl:32])[CH2:9]1)=[O:7])(C)(C)C.Cl>C(Cl)Cl>[Cl:32][C:14]1[CH:15]=[CH:16][C:17]([NH:19][C@@H:20]([C:23]2[CH:28]=[C:27]([CH3:29])[C:26]([Cl:30])=[C:25]([CH3:31])[CH:24]=2)[CH2:21][CH3:22])=[CH:18][C:13]=1[CH2:12][N:10]1[CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:11]1
Reactant: CC[C@@H](Nc1ccc(Cl)c(CN2CC(C(=O)OC(C)(C)C)C2)c1)c1cc(C)c(Cl)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](Nc1ccc(Cl)c(CN2CC(C(=O)O)C2)c1)c1cc(C)c(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of INT 58 (206 mg, 0.431 mmol) in CH2Cl2 (5 mL) was treated with HCl (4 M in dioxane, 0.43 mL, 1.726 mmol) and stirred at room temperature overnight. The mixture contained some starting material, so another portion of HCl (4 M in dioxane, 0.50 ml, 2.00 mmol) was added and stirring continued for 4 hours. Excess of HCl gas was removed by a stream of argon. The mixture was neutralized with 10% sodium bicarbonate solution then treated with 10% ammonium chloride solution and extracted first with CH2Cl2 then with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The title compound was purified by preparative UPLC (H2O/CH3CN).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:12]([C@@H:14]2[CH2:18][CH:17]([F:19])[CH2:16][N:15]2C(OC(C)(C)C)=O)=[O:13])[CH2:11][CH2:10][CH2:9]1>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1([C:12]([C@@H:14]2[CH2:18][CH:17]([F:19])[CH2:16][NH:15]2)=[O:13])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(F)C[C@H]1C(=O)N1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C([C@@H]1CC(F)CN1)N1CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added under ice cooling to a 30 mL chloroform solution of 2.20 g of the compound obtained in step 7-2, after which the reaction mixture was stirred for 2 hours at room temperature. After this, the reaction mixture was concentrated under reduced pressure to obtain 3.82 g of residue (pale yellow oily substance). This compound was used in the following reaction without being purified.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[CH:6]=1>C1COCC1>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])=[C:7]([CH3:15])[CH:6]=1
Reactant: CNC
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1S(=O)(=O)N(C)C
Yield: 100.7 %

Procedure:
To a mixture of 40% dimethylamine (aqueous, 2.5 mL, 20 mmol) in THF (2.5 mL) added 4-bromo-2-methylbenzenesulfonyl chloride (0.27 g, 1.0 mmol) with stirring. After 5h the reaction mixture was partitioned between DCM (50 mL) and water (50 mL), washed with water (2×50 mL) and brine (50 mL), dried (anhyd Na2SO4) and concentrated under reduced pressure to provide the title compound (0.28 g, quant) as a colorless liquid, which was used without purification in the next step. 1H-NMR (CDCl3) δ 7.74 (1H, d, J=8.3), 7.49 (1H, d, J=1.8), 7.46 (1H, dd, J=1.8, 8.3), 2.80 (6H, s), 2.60 (3H, s); Rf=0.38 (silica, 1:4 EtOAc/Hex).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:28]([OH:30])=[O:29])[NH2:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 85.9 %

Procedure:
Lysine stearate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 28.8 g of Nε-stearoyl lysine (yield 85.9%). This is designated Derivative A.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]/[CH3:25]>C([O-])([O-])=O.[Na+].[Na+].COCCOC.CCO>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](/[CH:23]=[CH:24]\[CH3:25])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(Br)cccc3[C@H]1CN(Cc1ccccc1)C2
Reactant: C/C=C\B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 160 °C

Procedure:
Tetrakis(triphenylphosphine)Pd(0) (0.021 mmol, 24.32 mg) was added in one portion to a mixture of cis-2-benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.421 mmol, 150 mg) and (Z)-prop-1-enylboronic acid (0.631 mmol, 54.2 mg) in 2 N aq Na2CO3 (1 ml), DME (1 ml) and EtOH (0.5 ml) The reaction mixture was heated under microwave irradiation at 160° C. for 900 seconds and then the mixture was filtered through celite. The resulting filtrate was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over Na2SO4 and conc in vauco to afford a brown oil that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford cis-2-benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole) (127 mg), m/z: 318.3 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(C)c2c(c1)CCN2
Reactant: CC[C@@H](COC)n1cc(Br)nc(Br)c1=O
Agent: Cl
Product: CC[C@@H](COC)n1cc(Br)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 115–117° C.; 1H NMR (300 MHz, CDCl3): δ 6.98 (s, 1 H), 6.66 (m, 1 H), 6.58 (d, J=2.2 Hz, 1 H), 5.00–4.90 (m, 1 H), 4.38 (t, J=8.1 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.2, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.7 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.92–1.70 (m, 2 H), 0.94 (t, J=7.4 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Br (M+H)+: 422.1079; Found m/z 422.1096.
Reaction SMILES: C[O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH2:16]([O:15][C@@H:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:20][C:21]1[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][CH3:34])=[CH:31][CH:32]=3)[O:24][C:25]=1[CH3:26])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:18])[CH3:17]
Reactant: CCc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CCO[C@@H](Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: CCO[C@@H](Cc1ccc2c(ccn2Cc2nc(-c3ccc(CC)cc3)oc2C)c1)C(=O)O
Yield: 47 %

Procedure:
Starting from (S)-2-ethoxy-3-(1H-indol-5-yl)-propionic acid methyl ester and 4-chloromethyl-2-(4-ethyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 47% yield as a colourless solid. MS: (M−H)− 431.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[C:12]([OH:14])=[O:13])=[C:6]([F:20])[C:5]([CH2:21][NH:22][C:23]([C:25]2[N:29](COCC[Si](C)(C)C)[CH:28]=[N:27][C:26]=2[Cl:38])=[O:24])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[C:12]([OH:14])=[O:13])=[C:6]([F:20])[C:5]([CH2:21][NH:22][C:23]([C:25]2[NH:29][CH:28]=[N:27][C:26]=2[Cl:38])=[O:24])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C(=O)O)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)cc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 3-({6-chloro-3-[({[4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]carbonyl}amino)methyl]-2-fluorophenyl}oxy)-5-cyanobenzoic acid (30 mg, 0.052 mmol) in DCM (2 ml) was added TFA (2 ml). The mixture was stirred for 30 min and the solvent was removed under vacuum. The crude product was purified by Reverse Phase HPLC (MeCN/water 0.1% formic acid) to give 20 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 8.02 (s, 1H) 7.58-7.79 (m, 2H) 7.49 (d, 1H) 7.23-7.43 (m, 2H) 4.63 (s, 2H). LC-MS (ES+) m/z 448.10, [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6](=[O:9])[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.Cl>C(OCC)C>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][N:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[C:6](=[O:9])[CH2:7][CH2:8][C:2]2=[O:1])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCCN2C(=O)CCC(=O)c3ccccc32)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C1CCC(=O)N(CCCCN2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.6 %

Procedure:
tert-Butyl 4-[4-(2,5-dioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)butyl]piperazine-1-carboxylate from Example 61 (8.28 mmol, 3.44 g) in diethyl ether (40 ml) was admixed with saturated ethereal HCl (30 ml) and the mixture was stirred at room temperature for 12 h. The reaction mixture was then filtered and the resulting residue was washed with diethyl ether to obtain 0.93 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:3]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:36]I>C1(C)C=CC=CC=1.CC#N>[F:1][C:2]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([F:11])[CH2:3][I:36]
Reactant: II
Reactant: OCC(F)(F)c1ncccn1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: FC(F)(CI)c1ncccn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
A homogeneous solution of 2,2-difluoro-2-pyrimidin-2-yl-ethanol (689 mg, 4.31 mmol), as prepared in the previous step, PPh3 (1.69 g, 6.44 mmol), and imidazole (590 mg, 8.67 mmol) in toluene (5.8 mL) and CH3CN (2.9 mL) was stirred at 0° C. for 5 min, and was then treated with I2 (1.61 g, 6.34 mmol) in two portions and stirred at 0° C. for another 5 min. The resulting brown opaque slurry was then heated at 90° C. for 19 h, and then allowed to cool to rt. The mixture was filtered, the beige filter cake was washed with toluene (3×10 mL), and the combined brown filtrates were concentrated. Silica flash chromatography of the residue (2:1 hex/EtOAc eluent) afforded the title compound as a pale yellow oil (849 mg, 73%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C@H:17]1[CH2:26][C:25]2[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[CH:23][CH:22]=[C:21]([Br:40])[C:20]=2[CH2:19][CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[Br:40][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28]2)=[C:25]2[C:20]=1[CH2:19][CH2:18][C@@H:17]([NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:26]2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c3c2C[C@H](N)CC3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)c3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
4-Morpholinobenzoic acid (0.50 g, 2.4 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) was dissolved in thionyl chloride (10 mL). After 2 min, the thionyl chloride was evaporated in vacuo and the residue was treated with toluene and again the solvent was evaporated in vacuo. Crude acid chloride (81 mg, 0.36 mmol) was dissolved in methylene chloride (10 mL) and added dropwise to a solution of tert-butyl (R)-4-(7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl)piperazin-1-carboxylate (140 mg, 0.34 mmmol) and triethylamine (71 μL, 0.51 mmol) in methylene chloride (10 mL). After the addition, the reaction was stirred at ambient temperature for 15 min and was then washed with a diluted aqueous solution of sodium hydrogen carbonate and the phases were separated. The organic phase was dried (Na2SO4), filtered and evaporated in vacuo and the residue was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent. Yield: 160 mg (79%) of a viscous colorless oil: [α]21D−11° (c=1, chloroform); TSPMS m/z (relative intensity)-599 and 601 (35, M+).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1>N1C=CC=CC=1>[CH3:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[C:12]3[C:28](=[O:35])[C:29]4[CH:30]=[CH:31][N:32]=[CH:33][C:34]=4[C:10]([C:11]=23)=[N:9]1
Reactant: CN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c4c(nn3C)-c3cnccc3C(=O)c24)cc1
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c3c(nn2C)-c2cnccc2C(=O)c13
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1M solution of N,N-dimethylethylenediamine in pyridine (0.10 mL) is added to a stirred suspension of 2-methyl-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (0.02 g) in dry pyridine (2 mL). After stirring at room temperature for one hour the reaction mixture is heated at 70° C. for 13 hours while additional amounts of N,N-dimethylethylenediamine solution (0.1; 0.05; 0.05 mL) are added after 2, 4 and 11 hours respectively. Pyridine and excess N,N-dimethylethylenediamine are removed by distillation at reduced pressure and the obtained residue is partitioned between CH2Cl2 (50 mL) and brine (10 mL) to which NaHCO3 saturated solution is added (1 mL). The organic solution is dried over anhydrous Na2SO4 and the solvent removed by distillation. The orange residue obtained is purified by silica-gel column chromatography (eluant: CHCl3 /MeOH 95/5 (30 mL) followed by CHCl3 /MeOH/NH4OH 90/15/0.5 (50 mL) to give 2-methyl-5-[[2-(dimethylamino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one (0.011 g) as a reddish orange solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([CH2:11]Br)=[CH:7][C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.[CH3:15][OH:16].C[O-].[Na+]>CO>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][O:16][CH3:15])=[CH:7][C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: Fc1cc(Br)c2oc(CBr)cc2c1F
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COCc1cc2c(F)c(F)cc(Br)c2o1
Yield: 80 %

Procedure:
The compound (489 mg, 1.50 mmol) of Step 1 of Example 54 was dissolved in methanol (7 mL), and a 25% sodium methoxide methanol solution (1.5 mL) were added thereto, and heated under reflux for 3 hours. The resultant was returned to room temperature, and the solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14]1COCC1.OS(O)(=O)=O>CO.O>[CH3:14][O:12][C:11]([C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8])=[O:13]
Reactant: Cc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To 5-methylisophthalic acid (Aldrich, 5 g, 27.7) in MeOH (37.5 ml)/THF (112.5 ml), conc. H2SO4 (1.25 ml) was added and stirred at 65° C. for 8 h. Reaction mixture was cooled to room temperature and solvent removed. Then reaction mixture was diluted with water and extracted with ethylacetate. Crude residue was column chromatographed to yield 2.5 g of 3-(methoxycarbonyl)-5-methylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7])#[N:2].S(=O)(=O)(O)[OH:13]>O.CC(C)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[C:6]([OH:13])=[O:7])#[N:2]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: O=S(=O)(O)O
Agent: [Cr+3]
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Chromium oxide (14.77 mmol; 1.48 g) was dissolved in a solution of sulfuric acid (1.1 mL) and water (3.4 mL) at 0° C. To this solution was added to a mixture of 3-cyano-4-fluorobenzaldehyde (13.4 mmol; 2.0 g) in acetone (17 mL) at 0° C. The reaction mixture was warmed to rt and stirred for 6 h. The reaction was then quenched with methanol (20 mL) and water (50 mL) and the product was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 2.25 g of product: 1H NMR (500 MHZ, CDCl3) δ 8.39 (d, J=5.0, 1H), 8.28-8.29 (m, 1H), 7.64 (t, J=8.9, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](N)=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.N([O-])=O.[Na+].[Na+].[I-:22].[OH-].[Na+]>OS(O)(=O)=O.O>[Cl:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][C:5]([I:22])=[CH:6][N:7]=1
Reactant: Nc1cnc(Cl)c(/C=C/c2ccncc2)c1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Clc1ncc(I)cc1/C=C/c1ccncc1
Reaction time: 5 h
Yield: 69.9 %

Procedure:
A solution of Example 21A (1.0 g, 4.3 mmol) in 30% H2SO4 (10 mL) at 0° C. was treated with NaNO2 (386 mg, 5.6 mmol), stirred for 5 hours, treated with a solution of NaI (2.1 g, 14 mmol) in H2O (2 mL), stirred for 2 hours, treated with additional NaI (2.1 g, 14 mmol), stirred for 2 hours, poured into 30% NaOH (aq.) (200 mL) at 0° C. and extracted three times with 10% methanol/ethyl acetate. The combined organic phases were dried (MgSO4), filtered, and concentrated. The residual solid was purified by flash column chromatography on silica gel with 70% ethyl acetate/hexanes to provide the desired product (1.03 g, 70%).
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:28][OH:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].Cl>O1CCCC1>[CH3:7][S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][N:28]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:29]3)=[CH:25][CH:26]=2)=[CH:14][CH:13]=1)(=[O:10])=[O:9]
Reactant: O=C=NC(=O)Cl
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(CNO)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
0.45 g (4 mmole) N-(chlorocarbonyl)isocyanate was added dropwise to a solution of 1.2 g (3.6 ml) 4-(2-{4-[hydroxyaminomethyl]phenoxy}ethyl)phenyl methanesulfonate in 20 ml anhydrous tetrahydrofuran at −5° C. and the mixture was stirred at −5° C. for 30 minutes. The reaction mixture was poured on to 2 M hydrochloric acid and extracted with ethyl acetate, dried (sodium sulfate), filtered and evaporated in vacuo. The residue was redissolved in ethyl acetate, and material that did not go into solution was filtered off. The filtrate was evaporated in vacuo, diethyl ether was added to give a white precipitate which was filtered off and recrystallized in diethyl ether/acetone to give 0.223 g of the desired product. The mother liquid was evaporated in vacuo and purified by chromatography on silica gel using dichloromethane:methanol (95:5) as eluent and crystallized in diethyl ether to give 0.09 g more of the desired product (total yield 0.384 g, 26.2%).