Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30](OCC)=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:36][CH2:37][C@H:38]([OH:40])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:36][CH2:37][C@H:38]([OH:40])[CH3:39])=[O:31])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-1-amino-2-propanol using methods similar to Example 563 to provide a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.09 (t, J=6.63 Hz, 3 H), 1.66-1.80 (m, 6 H), 2.19 (t, J=5.79 Hz, 2 H), 3.16-3.25 (m, 4 H), 3.34-3.48 (m, 2 H), 3.73-3.87 (m, 1 H), 4.17-4.24 (m, 4 H), 4.96 (d, J=4.63 Hz, 1 H), 7.11-7.17 (m, 2 H), 7.38-7.43 (m, 2 H), 8.00 (s, 1 H), 8.56 (s, 1 H), 10.43 (s, 1 H), 16.84 (s, 1 H); ES+ MS: 511 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[CH2:14][Br:16]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CBr

Procedure:
2.37 g (11.12 mmol) of 5-fluoro-2-methyl-3-nitrobenzoic acid methyl ester is added in 35 ml of carbon tetrachloride and mixed with 2.24 g (12.24 mmol) of N-bromosuccinimide and 5.4 mg of benzoyl peroxide. After four days of refluxing, the succinimide is suctioned off (glass-fiber filter) after cooling, and then the filtrate is spun in until a dry state is reached. Chromatography on a Flashmaster yields 2.47.g (75.9%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:27][CH3:28])=[O:4].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:26]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:27][CH3:28])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(Oc2ccccc2)cc1)O3
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.9 %

Procedure:
(S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (30 mg), Cu(OAc)2, (25 mg), phenyl boronic acid (32 mg) and molecular sieves suspended in 5 mL DCM. TEA (0.064 mL) added, reaction flushed with oxygen and stirred at room temperature for 20 hours. The resulting mixture poured onto EtOAc and 10% sodium carbonate. Organic layer washed 3 times with 10% sodium carbonate, dried over sodium sulfate and concentrated. Residue purified over silica (hexanes to 9:1 hexanes/EtOAc) to give (3S,8S)-3-(4-phenoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (22 mg). LCMS (m/z): 537.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23]3[N:24]=[CH:25][C:26]4[C:31]5[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:30]=5[N:29]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:27]=4[N:28]=3)=[N:20][CH:21]=2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.CO.C(O)C.C(OCC)C>[CH:37]1([N:29]2[C:27]3[N:28]=[C:23]([NH:22][C:19]4[N:20]=[CH:21][C:16]([N:13]5[CH2:12][CH2:11][CH:10]([CH2:9][OH:8])[CH2:15][CH2:14]5)=[CH:17][CH:18]=4)[N:24]=[CH:25][C:26]=3[C:31]3[CH:32]=[CH:33][N:34]=[C:35]([F:36])[C:30]2=3)[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: OCC1CCN(c2ccc(Nc3ncc4c5ccnc(F)c5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 27.5 %

Procedure:
Compound 282 (118 mg, 205 μmol) was dissolved in dry THF (3 mL). Tetrabutylammonium fluoride, 1.0M in THF (0.75 mL, 750 μmol) was added and the reaction was stirred at room temperature for 80 minutes. The resulting solution was added to aqueous K2CO3 (10%, 30 mL) and extracted with dichloromethane+10% methanol (2×30 mL). The combined organics were dried (MgSO4) and evaporated to give an orange oil. Silica gel chromatography (gradient elution ethyl acetate+2.5% TEA/0-5% methanol) afforded a yellow solid. This residue was taken up in methanol (1.5 mL) and HCl in ethanol (1.0M, 0.5 mL) was added. Diethyl ether (20 mL) was added to precipitate the product as a yellow solid, which was filtered and dried in vacuo to give compound 283 as a yellow solid (26 mg, 27%). 1H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1 H) 9.27-9.37 (m, 1 H) 8.11 (d, J=9.05 Hz, 1 H) 7.99-8.06 (m, 4 H) 7.48 (dd, J=9.17, 2.81 Hz, 1H) 5.46 (quin, J=9.11 Hz, 1 H) 4.50 (t, J=5.26 Hz, 2 H) 3.70 (d, J=11.98 Hz, 2 H) 2.61-2.71 (m, 2 H) 2.35 (d, J=12.72 Hz, 2 H) 2.10 (br. s., 2 H) 1.95-2.06 (m, 2 H) 1.77 (t, 4 H) 1.45-1.59 (m, 1 H) 1.28 (qd, J=12.23, 3.67 Hz, 2 H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)O)=O)=[CH:4][CH:3]=1.[NH2:19][C:20]([NH2:22])=[S:21].O.C(O)C>C(O)CCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:19][C:20](=[S:21])[NH:22][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccc(Br)cc1)C(O)c1ccc(Br)cc1
Solvent: CCO
Solvent: O
Solvent: CCCCCCO
Product: S=c1[nH]c(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)[nH]1

Procedure:
A mixture of 4,4'-dibromobenzoin (25 g, 0.068 mol) and thiourea (10.3 g, 0.14 mol) in hexanol (200 ml) was refluxed with azeotropic distillation of water for three hours. The solution was then cooled and ethanol (300 ml) was added. The mixture was further cooled and the small needles which formed were collected and washed with cold ethanol then ether and dried. Recrystallization of the product from ethyl acetate gave 4,5-bis-(4-bromophenyl)-1H-imidazole-2-thione, m.p. 288°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1.[Cl-].[NH4+]>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: BrCCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
15 g of sodium hydride at 60% in oil are suspended in 200 ml of anhydrous THF. A solution of 69.5 g of 3,4-dichlorophenylacetonitrile in 500 ml of THF is added dropwise over 30 minutes and then the reaction mixture is stirred at RT for 1 hour. The mixture is cooled to −20° C. and a solution of 85 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 100 ml of THF is added. The mixture is allowed to return to RT and after 2 hours it is poured over a solution of 50 g of ammonium chloride in 3 liters of water. The mixture is extracted with ether, washed with a saturated solution of sodium chloride, decanted, dried over MgSO4 and concentrated. The residue is chromatographed on silica gel, eluting with a mixture of toluene and an AcOEt gradient (3 to 5%). The pure product fractions are concentrated to give 77 g of expected product in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH3:2].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:9]1[CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:11])[N:7]=[CH:8]1
Reactant: CCOC(=O)Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cn(COCC[Si](C)(C)C)cn1
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of 383 gm (2.48 mmol) of 1H-imidazole-4-acetic acid ethyl ester (prepared according to the procedure of Bashkin et al; J. Org. Chem., 1990, 55, 5125-5132.) in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere was added 109 mg (2.73 mmol) of 60% sodium hydride/oil dispersion. The resulting mixture was stirred for 30 minutes at which time was added dropwise by syringe 0.53 mL (3.0 mmol) of 2-trimethylsilylethoxymethyl chloride. The reaction mixture was stirred for 4 hours at room temperature then diluted with 150 mL of ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent removed under vacuum. The resulting material was purified by column chromatography on silica gel, eluting with chloroform/10% concentrated ammonium hydroxide in methanol (96:4), to afford 342 mg (48%) of the products in a 1.5:1 ratio of N-1:N-3 imidazole regioisomers as a colorless oil. FAB-MS: calculated for C13H24N2O3Si 284; found 285 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 0.00 (s, 18H), 0.90 (m, 4H), 1.25 (t, 7 Hz, 6H), 3.45 (m, 4H), 3.65 (s, 2H), 3.70 (s, 2H), 4.15 (m, 4H), 5.20 (s, 2H), 5.35 (s, 2H), 7.00 (s, 1H), 7.02 (s, 1H), 7.65 (s, 1H), 7.97 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](=O)[N:13]([C:17]1[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=1[NH2:25])[CH:14]([CH3:16])[CH3:15])(C)(C)C.Cl.O1CCOCC1>CO>[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[N:13]([CH:14]([CH3:16])[CH3:15])[C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][C:18]=2[N:25]=1
Reactant: CC(C)N(C(=O)CCCCNC(=O)OC(C)(C)C)c1cc(C#N)ccc1N
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1c(CCCCN)nc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
The compound (44.1 mg) obtained in Example 47-1 was dissolved in anhydrous methanol (1.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (26.0 mg) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:12].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:24])=[CH:21][N:22]=2)[N:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][C:9]=3[F:11])[N:6]([CH3:12])[N:5]=[CH:4]4)([OH:25])[CH3:24])=[CH:21][N:22]=2)[N:19]=1
Reactant: Cn1ncc2c(F)cc(F)cc21
Reactant: CC(=O)c1cnc2ccc(Cl)nn12
Solvent: C1CCOC1
Product: Cn1ncc2c(F)c(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Reaction time: 1 h

Procedure:
N-BuLi, 6.88 mL, was added dropwise to a solution of 4,6-difluoro-1-methyl-1H-indazole ((xvi), 1.68 g, 10 mmol) in dry THF (50 mL) at −78° C. The solution was stirred at this temperature for 1 h, and then the solution of 1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)ethanone (CAS 90734-71-7, 1.95 g, 10 mmol) in 50 mL THF was added dropwise at −70/75° C. After stirring additional 3 h at −70/75° C. the RM was quenched with NH4C110%, and at 0° C. diluted with water, and extracted with EtOAc (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to afford the title compound as a yellow foam (tR 4.40 min (conditions 5), MH+=364.2, 1H-NMR in DMSO-d6: 8.16 (d, 1H); 8.11 (s, 1H); 7.85 (s, 1H); 7.30 (d, 1H); 7.22 (d, 1H); 6.26 (s, 1H); 3.96 (s, 3H); 2.12 (d, 3H)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17]>CS(C)=O.CCOC(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(F)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a warm solution of piperazine (7.78 g, 90 mmol) in DMSO (40 mL) was added dropwise 1,2-difluoro-4-nitrobenzene (2.0 mL, 18.07 mmol). The solution was stirred at 70° C. for 2 h, cooled 10 to room temperature, diluted with EtOAc, washed with H2O, brine, dried (Na2SO4), filtered and solvent removed in vacuo to give the title compound (4.05 g, 17.98 mmol, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 3.03-3.09 (m, 4H) 3.26-3.29 (m, 4H) 6.91 (t, J=8.8 Hz, 1H) 7.91 (dd, J=13.1, 2.6 Hz, 1H) 7.96-8.01 (m, 1H). MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: C([N:4]1[CH:8]([C:9](=[O:11])[CH3:10])[CH2:7][CH2:6][C:5]1=[O:12])(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>C(OCC)(=O)C.CO>[C:9]([CH:8]1[NH:4][C:5](=[O:12])[CH2:6][CH2:7]1)(=[O:11])[CH3:10]
Reactant: CC(=O)C1CCC(=O)N1C(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)C1CCC(=O)N1
Temperature: 25 °C
Yield: 48 %

Procedure:
In a round bottom flask, Compound 5 (2.2 g, 13×10−3 mol) is treated with a solution of K2CO3 (5.6 g, 40×10−3 mol, in 20 mL of water), with magnetic stirring at room temperature. The progress of the reaction is followed by TLC (eluent: ethyl acetate/methanol, 98/2). After stirring for 3.5 hrs, the reaction is complete. The reaction mixture is neutralized (pH=7) by adding 1N hydrochloric acid and then freeze-dried for 16 hrs. The organic residue is then extracted with CH2Cl2 (40 mL), filtered and then concentrated under reduced pressure to provide a brown viscous liquid. Purification was carried out on a silica gel column (eluent: ethyl acetate/methanol, 98/2). Compound 6 is obtained after such purification as a white powder.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7](N)[CH:6]=[CH:5][N:4]=1)[CH3:2].[N+]([O-])(O)=[O:11].N([O-])=O.[Na+]>O>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCc1cc(N)ccn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
282.1 g (2.3 mol) 2-Ethyl-pyridin-4-ylamine are dissolved in concentrated HNO3 (789 mL, 11.561 mol) and H2O (1.5 L). Then a solution of NaNO2 (238.9 g, 3.468 mol) in H2O (600 mL) is slowly added to the solution over 2 h at 0° C. After the addition, the mixture is warmed to RT and stirred for additional 2 h. The reaction mixture is stored at −2° C. overnight. The precipitate is collected by filtration, and dried in vaccuo to afford the title compound. Yield: 155.1 g, (54%)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8]1.C(N(CC)CC)C.O>C1COCC1>[CH3:16][C:9]1([CH3:17])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(N)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC1(C)CC(NS(C)(=O)=O)c2ccccc21
Reaction time: 2 h
Yield: 88.6 %

Procedure:
with ice-cooling, 4.0 g (34.7 mmol) of methanesulfonyl chloride were added dropwise to a solution of 5.1 g (31.6 mmol) of 1-amino-3,3-dimethylindan and 12.8 g (126.4 mmol) of triethylamine in 100 ml of THF. After 2 h at RT, 100 ml of water were added, the reaction mixture was concentrated to about 50 ml and admixed with 100 ml of water and the precipitate was filtered off with suction, rinsed with water and dried under reduced pressure. This procedure gave 6.7 g of 3,3-dimethyl-1-methylsulfonylaminoindan; m.p. 117-119° C.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Br:11][C:12]([CH3:17])([CH3:16])[C:13](Br)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:13](=[O:14])[C:12]([Br:11])([CH3:17])[CH3:16])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(C)(C)Br)cc1OC
Yield: 42.9 %

Procedure:
A mixture of veratrole (1,3-dimethoxybenzene) (13.8 g), 2-bromoisobutyryl bromide (23.0 g) and aluminium chloride (14.0 g) was heated for 1 hour at 70°-80° C. After cooling, ice and hydrochloric acid were added to the reaction mixture which was then extracted with ether. The extract was washed first with water and then with 1N NaOH-solution, dried and the solvent evaporated in vacuo, yielding a pale yellow oil (12.3 g).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:29])[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])[CH:20]=[C:19]([Cl:30])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[Cl:30][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[O:29]
Reactant: CC(C)N(C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1

Procedure:
A solution of {2-[3-chloro-5-(isopropyl-methyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.060 g) in dichloromethane (4 ml) and trifluoroacetic acid (4 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc to give the title compound as a yellow gum (0.061 g).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.[OH-].[Na+].OO>[Na+].C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1S([O-])(=O)=O.CO>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: O=C1c2ccccc2C(=O)c2cc(S(=O)(=O)[O-])ccc21
Agent: OO
Agent: [Na+]
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 52.5 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
A one liter flask equipped with a thermometer, stirrer and condenser is charged with 40 grams 6,13-dihydroquinacridone, 0.3 grams pyrazolylmethylquinacridone, 250 ml methanol and 52.8 grams 50% aqueous sodium hydroxide. The mixture is stirred under a slow flow of nitrogen at 50-55° C. for one hour, generating 6,13-dihydroquinacridone disodium salt. 0.6 grams anthraquinone-2-sulfonic acid sodium salt are added and the mixture is heated to reflux temperature. 73.5 grams of an aqueous 16.9% hydrogen peroxide solution are added into the reaction mixture with a peristaltic pump at a rate of 0.4 ml/minute maintaining reflux under a slow nitrogen flow over 2 hours and 35 minutes. The resulting pigment suspension is further stirred for 1 hour at reflux; then filtered. The presscake is washed with hot water and then dried, yielding 38.9 grams beta quinacridone pigment. This product shows similar good pigment properties and similar color characteristics to the beta quinacridone obtained following the procedure of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[C:10]([CH:26]2[CH2:28][CH2:27]2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2]>CC(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]([OH:29])/[CH:7]=[CH:8]/[C:9]1[C:10]([CH:26]2[CH2:28][CH2:27]2)=[N:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:2]
Reactant: CCOC(=O)CC(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Solvent: CC(C)O
Product: CCOC(=O)CC(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of (E)-5-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-oxo-pent-4-enoic-acid-ethylester (105.8 mg, 0.262 mmol) and Ru[(1R,2R)-p-TsNCH(C6H5)CH(C6H5)NH](η6-p-cymene) (6.2 mg, 0.104 mmol) in 2-propanol (2.6 ml) is stirred at 23° C. for 72 h. The reaction mixture is concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel using a 4:1 hexane-MTBE (methyl-tert-butyl-ether) mixture as eluent to afford of (E)-5-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-3-hydroxy-pent-4-enoic-acid-ethylester.
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19]CC)=[O:18])C>C(O)C>[NH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:15]([OH:14])[C:16]([C:17]([OH:19])=[O:18])=[CH:22][N:8]=2)=[CH:5][CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=C(N)c1ccc(N)cc1
Agent: [Na]
Solvent: CCO
Product: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reaction time: 0.08 h
Yield: 102671.1 %

Procedure:
A solution of 14.8 g (0.642 mmol) of sodium in 750 ml of dry ethanol is stirred at 0° and 44.6 g (0.214 mmol) of 4-aminobenzamidine .2HCl [Shaw and Cooley, J. Am. Chem. Soc., 79, 3561 (1957)] is added. The mixture is stirred 5 minutes under nitrogen and 46.2 g (0.214 mmol) of diethyl ethoxymethylenemalonate is added. After stirring for 30 min, the mixture is refluxed for 4 hrs and allowed to stand overnight at room temperature. The salt is filtered and washed with isopropanol. The salt is suspended in 214 ml of 2 N potassium hydroxide and stirred at 70° C. for 4 hrs. After treating with a small amount of charcoal, the filtrate is added to 325 ml of 2 N HCl with stirring. The acid is filtered, washed with water, ethanol, and ether, and dried to give 50.8 g of the title compound, mp 312°- 314° C. dec. The product is recrystallized from dimethylacetamide-water to give 44.5 g mp 313°-314° C. dec.