Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:31]=[O:32]>O>[Br:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:11][C:4]=2[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:31]=[O:32]
Reactant: CCCN(CCC)C1CCc2c(cc3cc[nH]c3c2Br)C1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCCN(CCC)C1CCc2c(cc3c(C=O)c[nH]c3c2Br)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (9-Bromo-5,6,7,8-tetrahydro-1H-benzo[f]indol-6-yl)-dipropyl amine (50 mg, 0.14 mmol) in N,N-dimethyl formamide (3 mL) was cooled to 0° C. To this solution was added a cooled solution of phosphorus oxychloride (26 μL, 0.28 mmol) in N,N-dimethyl formamide (1 mL), which had been prepared 20 minutes previous to use. The mixture was stirred at ambient temperature for 30 minutes and then for 30 minutes at 50° C. an additional 30 minutes. The reaction mixture was then treated with a 1M sodium hydroxide solution (5 mL) with heating and stirring maintained for an additional hour. After cooling, the solution was diluted with water (25 mL) and extracted with several portions of diethyl ether. The combined etheral extracts were washed with water, brine, dried over magnesium sulfate, and the solvent evaporated. The residue was chromatographed on a silica column, using methanol as the eluant. This was then repeated with diethyl ether as eluant. The yield of the pure title compound was 50 mg (95%).:
Reaction SMILES: C[C:2]1([N:8]2[C:12]([C:13]3[S:25][C:16]4[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=4[CH:14]=3)=[CH:11][N:10]=[CH:9]2)C=CC=CC1.[I:26]C1N=CN(C)C=1C1SC2N=CN=C(SC)C=2C=1>>[I:26][C:11]1[N:10]=[CH:9][N:8]([CH3:2])[C:12]=1[C:13]1[S:25][C:16]2[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=2[CH:14]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: CSc1ncnc2sc(-c3c(I)ncn3C)cc12
Product: Cn1cnc(I)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-(4-iodo-1-methyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 93) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (273 mg, 85%);
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[N:7][C:8](Cl)=[N:9]2)=[C:4]([Cl:15])[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1>C(O)(C)C>[Br:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[O:24])=[CH:21][CH:22]=3)=[N:9]2)=[C:4]([Cl:15])[CH:3]=1
Reactant: COc1c(Br)cc(Cl)c2cnc(Cl)nc12
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: CC(C)O
Product: COc1c(Br)cc(Cl)c2cnc(Nc3ccc(C(=O)N4CCOCC4)cc3)nc12
Temperature: 90 °C

Procedure:
To 7-bromo-2,5-dichloro-8-methoxyquinazoline (1 eq) was added (4-aminophenyl) (morpholino)methanone (1 eq) in isopropanol and the mixture was heated to 90° C. for 16 h. The solid formed was filtered to give (4-(7-bromo-5-chloro-8-methoxyquinazolin-2-ylamino)phenyl) (morpholino)methanone and was confirmed by LC/MS. ES/MS m/z 478 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][N:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:17]([OH:19])=[O:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:34]O>>[CH2:5]([O:12][C:13]([NH:15][C@@H:16]([CH2:20][N:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:17]([O:19][CH3:34])=[O:18])=[O:14])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(N[C@@H](CN(c1ccccc1)c1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](CN(c1ccccc1)c1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
6.5 ml (89.1 mmol) of thionyl chloride were added dropwise, at −5° C., to 75 ml of methanol and the mixture was stirred for 15 min. 3.6 g (9.22 mmol) of 2-benzyloxycarbonylamino-3-diphenylaminopropionic acid (3), dissolved in 75 ml of methanol, were then added and the mixture was stirred at room temperature for a further 3 hours (h). After the solvents had been evaporated, the residue was taken up in ethyl acetate and extracted with sodium carbonate solution. The purification by means of flash chromatography (n-heptane/ethyl acetate 7:3) yielded 2.76 g (50% yield) of methyl 2-benzyloxycarbonylamino-3-diphenylaminopropionate (4).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[CH2:22]([N:24]([CH2:39][CH3:40])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:23]>C(O)C.N1CCCCC1>[CH2:39]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (73.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 2,4-dimethyl-5-[2-oxo-4-(4-trifluoromethoxy-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (75.6 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:14](=[O:19])C(Cl)(Cl)Cl)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[NH2:20][C:21]1[C:29]([Br:30])=[CH:28][C:27]([Br:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.CS(Cl)(=O)=O>C(#N)C.O>[Br:1][C:2]1[N:3]=[C:4]([C:14]2[O:19][C:23](=[O:24])[C:22]3[CH:26]=[C:27]([Br:31])[CH:28]=[C:29]([Br:30])[C:21]=3[N:20]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: O=C(c1nc(Br)cn1-c1ncccc1Cl)C(Cl)(Cl)Cl
Reactant: Nc1c(Br)cc(Br)cc1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1oc(-c2nc(Br)cn2-c2ncccc2Cl)nc2c(Br)cc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
To a solution of 0.50 g of 1-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-2,2,2-trichloroethanone and 0.37 g of 2-amino-3,5-dibromobenzoic acid in 10 ml of acetonitrile was added 0.43 ml of triethylamine. The resulting mixture was stirred at room temperature for 1 day. Thereto 0.12 ml of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.29 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-imidazol-2-yl]-6,8-dibromo-4H-3,1-benzoxazine-4-one of the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[C:18]=1[NH2:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:8][N:9]=2)=[O:13])[C:18]=1[NH2:24]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: O=C(O)c1n[nH]c2ncc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)c2n[nH]c3ncc(Br)cc23)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid Compound 1c (0.3 g, 1.17 mmol), 2,3-diamino-benzoic acid methyl ester Compound 8a (3.43 g, 20.64 mmol), HATU (7.85 g, 20.66 mmol), DIPEA (8.64 mL, 62 mmol) in DMF (250 mL) was stirred at room temperature overnight. The solvent was removed and the residue was purified by silica gel chromatography (10% to 90% of ethyl acetate in hexanes) to yield 2-amino-3-[(5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carbonyl)-amino]-benzoic acid methyl ester Compound 8b (5.1 g, 63% yield) as a colorless gel. 1H NMR (300 MHz, CD3OD) δ 9.03 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 7.58 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.8 Hz), 3.49 (s, 3H); MS (ESI) m/z: 391 (M+H+).
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:26])[CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1)[C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH2:3][CH3:4])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.ClCCl>[CH:1]([NH:5][C:6]([CH:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([C:22]([F:24])([F:25])[F:23])[CH:15]=1)[C:8]([CH3:11])([CH3:12])[CH2:9][O:10][S:28]([CH3:27])(=[O:30])=[O:29])=[O:26])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(C)NC(=O)C(Oc1ccc(C#N)c(C(F)(F)F)c1)C(C)(C)COS(C)(=O)=O
Reaction time: 3.5 h

Procedure:
To a stirring solution comprised of two (2) N-sec-butyl-2-(4-cyano-3-trifluoromethyl-phenoxy)-4-hydroxy-3,3-dimethyl-butyramide diastereomers (1.63 g; 4.38 mmol) in pyridine (10 mL) at 0° C. under a nitrogen atmosphere is added methanesulfonyl chloride (0.75 g; 6.5 mmol). The reaction mixture is stirred cold for 3.5 hours. The reaction mixture is diluted with dichloromethane and is washed with 1N aqueous hydrochloric acid and with brine. The organic phase is dried over anhydrous magnesium sulfate and is concentrated in vacuo (the water bath temperature is not raised above 23° C.) to afford 1.892 g of a foam; HPLC UV purity: 99.3% (two diastereomers.)
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[C:27]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)[CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCN(CC=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 1C (10.00 g, 23.4 mmol) in tetrahydrofuran/methanol (100/50 mL) was added solution of lithium hydroxide monohydrate (2.59 g, 70 mmol) in water (30 mL). The reaction mixture was stirred at 60° C. for 16 hours, then was cooled to room temperature and the organic solvents were concentrated. The white solid residue was dissolved in hot water and then the product was neutralized with HCl (3 equivalents). After cooling to room temperature, the precipitate was filtered off, washed with water and dried in a vacuum oven overnight at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:6]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: Nc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(N(c2ccc(Cl)cc2)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
Bis(p-nitrophenyl)-p-chlorophenylamine (3.70 grams, 0.010 mol) obtained by the Ullmann condensation of p-chloroaniline and p-nitroiodobenzene was mixed with 125 ml of N,N-dimethylformamide and 2,50 grams (0.045 mol) of iron powder, and dilute hydrochloric acid prepared using 1.5 ml of concentrated hydrochloric acid and 4 ml of water was added to the mixture which was then reacted for 1 hour at 100° C. The mixture was then neutralized by the addition of a saturated aqueous solution of sodium carbonate and the resulting mixture was filtered while hot. The filtrate was poured into 1.5 liters of ice water and 2.33 grams (yield 69%) of p-aminophenyl-p-nitrophenyl-p-chlorophenylamine was obtained on recovering the material which precipitated out by filtration.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14](I)[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:35]1([O:44][P+](N(C)C)(N(C)C)N(C)C)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1.[CH3:55][C:56]1([CH3:68])[O:60][C@H:59]([CH2:61][N:62]2[CH:66]=[CH:65][C:64]([NH2:67])=[N:63]2)[CH2:58][O:57]1>CN(C)C=O.C(OCC)(=O)C>[N:35]1([O:44][C:14]2[CH:13]=[N:12][N:11]([CH:7]([CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:8]([NH:67][C:64]3[CH:65]=[CH:66][N:62]([CH2:61][C@@H:59]4[CH2:58][O:57][C:56]([CH3:68])([CH3:55])[O:60]4)[N:63]=3)=[O:10])[C:16](=[O:17])[CH:15]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(I)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(On4nnc5ccccc54)cc3=O)n2)O1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid (Intermediate 85, 1.44 g, 3.98 mmol) in N,N-dimethylformamide (18 mL, 0.22M) at 25° C. was treated with N,N-diisopropylethylamine (2.0 mL, 12.10 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (2.64 g, 5.97 mmol) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4, 0.88 g, 4.46 mmol). The reaction was stirred at 25° C. over 3 nights. After this time, the reaction was diluted with ethyl acetate (150 mL) and was washed with a saturated aqueous ammonium chloride solution (150 mL), a saturated aqueous sodium bicarbonate solution (150 mL) and a saturated aqueous sodium chloride solution (150 mL), dried over magnesium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography (AnaLogix 80 g, 25-75% gradient ethyl acetate/hexanes) afforded 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (1.11 g, 51%) as an off-white solid as a mixture of diastereomers.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[C:11]([CH3:19])[N:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][NH2:32])[CH:21]=1>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:12]=[C:11]([CH3:19])[N:10]=1
Reactant: NCCOCCCc1cccnc1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.1 mL, 44 mmol) was added to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (7.50 g, 36.2 mmol), prepared as described in Part A of Example 1, in anhydrous DMF (160 mL). Neat 2-[3-(pyridin-3-yl)propoxy]ethylamine (6.60 g, 36.6 mmol) was then added, and the mixture was stirred at room temperature for 1.5 hours. The volatiles were then removed under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with 2% aqueous potassium bicarbonate (1×), water (1×), and brine (1×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (600 g, eluting with methanol:ethyl acetate in various ratios) to afford an oil which was dried under reduced pressure to yield 4.9 g of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:17]=[CH:16]SC=2)=[N:8]1)=[O:6].ClC1C=C(C=CC=1Cl)[C:26](N1CCCC(C2SC=CC=2)=N1)=[S:27].ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=S>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[S:27][CH:26]=[CH:16][CH:17]=2)=[N:8]1)=[O:6]
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Reactant: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1

Procedure:
1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine and 1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.
Reaction SMILES: CCOCC.Br[CH2:7][C:8](=O)[CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].[CH:22]([NH2:24])=[S:23]>CCO>[S:23]1[CH:7]=[C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[N:24]=[CH:22]1
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: NC=S
Solvent: CCOCC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1cscn1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ether (7.5 mL) was added to the above solution of 2-(3-bromo-2-oxopropyl)-1H-isoindole-1,3(2H)-dione and cooled to 0° C. in an ice/NaCl salt bath. Then thioformamide (European Journal of Medicinal Chemistry, 2004, 39, 867-872.) (1.20 g) in EtOH (8 mL) was added, and the reaction was stirred overnight. The solvents were evaporated and the reaction mixture was purified by RP-HPLC to provide 2-(1,3-thiazol-4-ylmethyl)-1H-isoindole-1,3(2H)-dione as a white solid. LCMS: (M+H)+=245.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH2:20]C)=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: NCCCCC(=O)O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)NCCCCC(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
5-aminopentanoic acid hydrochloride (1 g, 6.5 mmol), and potassium carbonate (6.5 g, 47 mmol) were dissolved in water (15 ml) and dioxane (5 ml) then cooled to 0° C. Ethyl chloroformate (3 ml, 31.5 mmol) was added over 30 seconds, then the mixture was stirred for 4 hours at 0° C. Conc. HCl was added until acidic then the mixture was diluted with water and extracted with ether. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)amino]pentanoic acid as a white powder (1.07 g).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.1 g) and triethylamine (425 mg) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (252 mg) at ice-bath temperature. After 2 hours, the reaction mixture was washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on silica gel using ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (988 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.O>CC(C)=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[O:24])=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)cc2)cc1
Yield: 91.9 %

Procedure:
To a solution of 9.97 g of 4-methoxybenzenesulfonamide in 54 ml of acetone were added 54 ml of a 1N sodium hydroxide solution. With stirring, a solution of 11.55 g of 4-bromophenylisocyanate in 50 ml of acetone was added. After stirring at room temperature for three days, the reaction mixture was filtered and 55 ml of 1N hydrochloric acid were added to the filtrate providing a fine white precipitate. Two hundred milliliters of water were added, and the solid was recovered by filtration to provide 18.85 g of the desired title product.
Reaction SMILES: Br([O-])(=O)=O.[Na+].[CH3:6][C:7]1[CH:12]([OH:13])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:14])[C:8]=1/[CH:16]=[CH:17]/[C:18](/[CH3:47])=[CH:19]/[CH:20]=[CH:21]/[C:22](/[CH3:46])=[CH:23]/[CH:24]=[CH:25]/[CH:26]=[C:27](\[CH3:45])/[CH:28]=[CH:29]/[CH:30]=[C:31](\[CH3:44])/[CH:32]=[CH:33]/[C:34]1[C:39]([CH3:41])([CH3:40])[CH2:38][CH2:37][CH:36]([OH:42])[C:35]=1[CH3:43]>O.ClCCCl.BrBr>[CH3:43][C:35]1[C:36](=[O:42])[CH2:37][CH2:38][C:39]([CH3:40])([CH3:41])[C:34]=1/[CH:33]=[CH:32]/[C:31](/[CH3:44])=[CH:30]/[CH:29]=[CH:28]/[C:27](/[CH3:45])=[CH:26]/[CH:25]=[CH:24]/[CH:23]=[C:22](\[CH3:46])/[CH:21]=[CH:20]/[CH:19]=[C:18](\[CH3:47])/[CH:17]=[CH:16]/[C:8]1[C:9]([CH3:15])([CH3:14])[CH2:10][CH2:11][C:12](=[O:13])[C:7]=1[CH3:6]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(O)CCC2(C)C)C(C)(C)CCC1O
Agent: BrBr
Agent: [Na+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: O
Solvent: ClCCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)CCC2(C)C)C(C)(C)CCC1=O
Yield: 91.3 %

Procedure:
1.5 g of sodium bromate dissolved in 20 ml of water is added to 1.5 g of isozeaxanthin dissolved in 250 ml of 1,2-dichloroethane. While stirring, 10 ml of 1,2-dichloroethane in which 30 mg of bromine is dissolved is dripped in over a period of 30 minutes. The pH of the aqueous phase is 5.6. After stirring for 1 hour at room temperature, the phases are separated, the 1,2-dichloroethane is washed with sodium bicarbonate solution and water and dried, and the solvent is distilled off under reduced pressure. 20 ml of methanol is added to the residue and the whole stirred for 10 minutes at 50° C. After cooling, filtration gives 1.36 g (92% of theory) of canthaxanthin.