Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=1[NH2:19]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([N:19]([C:4](=[O:5])[C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[C:18]1[C:17]([F:20])=[CH:16][N:15]=[CH:14][C:13]=1[F:12])=[O:5]
Reactant: Nc1c(F)cncc1F
Reactant: O=C(Cl)c1c(F)cccc1Cl
Solvent: c1ccncc1
Product: O=C(c1c(F)cccc1Cl)N(C(=O)c1c(F)cccc1Cl)c1c(F)cncc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Chloro-6-fluorobenzoyl chloride (13.6 g, 71.6 mmol) was added dropwise, over 10 minutes, to a solution of 3,5-difluoro-pyridin-4-ylamine (7.7 g, 59.3 mmol) in pyridine (100 mL) at 0° C. under argon and the reaction mixture was stirred at 0° C. for 3 hours. The volatiles were removed under reduced pressure and the resultant residue was treated with 1N HCl (100 mL). The resultant suspension was stirred at room temperature for 2 hours and then the solid was collected by filtration, washing with water. A mixture of 2-chloro-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide, LCMS (Method E): RT=2.83 min, m/z: 287 [M+H+], and of 2-chloro-N-(2-chloro-6-fluorobenzoyl)-N-(3,5-difluoropyridin-4-yl)-6-fluorobenzamide LCMS (Method E): RT=3.96 min, m/z: 443 [M+H+], (23 g) was obtained which was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]4)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[C:30]([NH2:35])[CH:29]=1>>[NH2:35][C:30]1[CH:29]=[C:28]([F:27])[CH:33]=[CH:32][C:31]=1[NH:34][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: COc1ccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc2c1
Reactant: Nc1ccc(F)cc1N
Product: COc1ccc2c(Oc3ccc4c(C(=O)Nc5ccc(F)cc5N)cccc4c3)ccnc2c1
Yield: 73 %

Procedure:
The title compound (33.1 mg, 73% yield) was prepared as a brown solid from 6-(7-methoxyquinolin-4-yloxy)-1-naphthoic acid (34.5 mg, 0.1 mmol) and 4-fluoro-o-phenylenediamine (15.1 mg, 0.12 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 3.95 (s, 3H, —OCH3), 5.27 (s, 2H, benzene-NH2), 6.41 (td, J=2.5 and 8.4 Hz, 1H, Ar—H), 6.57-6.61 (m, 2H, Ar—H), 7.30-7.36 (m, 2H, Ar—H), 7.45 (d, J=2.2 Hz, 1H, Ar—H), 7.56 (dd, J=2.2 and 9.2 Hz, 1H, Ar—H), 7.65 (t, J=7.6 Hz, 1H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07 (d, J=8.3 Hz, 1H, Ar—H), 8.24 (d, J=9.1 Hz, 1H, Ar—H), 8.43 (d, J=9.2 Hz, 1H, Ar—H), 8.65 (d, J=5.1 Hz, 1H, Ar—H), 9.75 (s, 1H, benzene-NH). LC-MS (m/z) 454 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([F:27])[CH2:23]1)=[O:21])=O)(C)(C)C>ClCCl>[F:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][NH:15]2)=[O:21])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CC[C@@H](F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1CCCN1)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of (S)-2-((R)-3-fluoro-pyrrolidin-1-ylcarbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 2.4 mmol) in dichloromethane (5 mL). After stirring at room temperature for 2 h, the reaction mixture was concentrated. The residue was dissolved in methanol-water (1:1), neutralized to pH>10 with OH− formed resin. After concentration, 400 mg (89%) of ((R)-3-fluoro-pyrrolidin-1-yl)-(S)-pyrrolidin-2-yl-methanone was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:26]([C@H:33]1[N:38]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH:36]=[C:35]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[C@@H:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)[C@H](Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 45 %

Procedure:
A mixture of (R)-1-methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (0.515 g, 1.5 mmol), (R)-tert-butyl 6-benzyl-4-(((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.900 g, 2.13 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.309 g, 0.375 mmol) and K2CO3 (0.622 g, 4.50 mmol) in 1,4-dioxane (15 mL) and water (5 mL) was heated at 90° C. for 4 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 6-benzyl-4-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.330 g, 45%).
Reaction SMILES: [F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=O)[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1.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.[CH2:59]([CH2:61][NH2:62])[OH:60]>CN(C=O)C>[F:1][CH:2]([CH3:25])[CH2:3][O:4][C:5]1[C:10]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([NH:62][CH2:61][CH2:59][OH:60])=[O:24])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Reactant: NCCO
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: Cc1c(C(=O)NCCO)sc2ncnc(Nc3cccnc3OCC(C)F)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(2-(2-Fluoropropoxy)pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (36.2 mg), HATU (42 mg) and Hünig's base (34 μl) were dissolved in DMF (2 ml) and ethanolamine (9 μl) was added. The reaction was stirred at room temperature for 2 h. The reaction mixture was purified directly by chromatography.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=CC=C[CH:2]=1.[OH:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]=1[N+:34]([O-:36])=[O:35].C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[CH3:27][C:25]1[N:24]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:23](=[O:33])[C:22]([N+:34]([O-:36])=[O:35])=[C:21]([O:20][CH:1]([CH3:6])[CH3:2])[CH:26]=1
Reactant: COC(=O)Cn1c(C)cc(O)c([N+](=O)[O-])c1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: c1ccccc1
Solvent: CC(C)O
Product: COC(=O)Cn1c(C)cc(OC(C)C)c([N+](=O)[O-])c1=O
Reaction time: 48 h

Procedure:
A solution of 11.38 g (43.4 mmol) of triphenylphosphine in 80 ml of benzene is cooled to 0° C. and 10 g (41.3 mmol) of methyl 4-hydroxy-6-methyl-3-nitro-2-oxo-1,2-dihydropyridine-1-acetate and 3.30 ml (43.37 mmol) of isopropanol are added. 6.83 ml (43.4 mmol) of diethylazodicarboxylate are then added dropwise and the mixture is left stirred for 48 hours. The reaction medium is washed successively with 50 ml of a saturated sodium hydrogen carbonate solution, 50 ml of water and 50 ml of a saturated sodium chloride solution. The medium is dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane:methanol (98:2) mixture.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@H]1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@H]1N
Reaction time: 0.67 h
Yield: 8.9 %

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.7 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.62 g), DBU (0.43 g) and anhydrous acetonitrile (30 ml) was refluxed for 52 hours. After cooling, the resulting precipitate was collected by filtration, washed with chilled acetonitrile and this was added to concentrated hydrochloric acid-methanol (1:1, 5 ml) and stirred for 40 minutes at elevated temperature. The reacting mixture was collected by filtration, washed with chilled water sufficiently and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:3) to give the title compound (0.076 g) as pale yellow prisms, mp 268°-270° C. (decompd.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13].[CH:14]#[C:15][CH2:16][CH2:17][CH2:18]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]#[C:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: C#CCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
The synthesis of (S7-3) was carried out following the method described in Synthesis, No. 9, 1439 (2004). At first, 38.3 g of 1-chloro-6-bromo-2-naphthol (S1-2), 5.2 g of PdCl2(PPh3)2, 0.71 g of copper iodide and 400 ml of triethylamine were added to a reactor in nitrogen atmosphere, stirred at room temperature, added with 35.8 g of 1-heptyne (S7-2) and then refluxed for 6 hours. The reaction solution was cooled to room temperature and distilled under a reduced pressure to remove the solvent, and then the residue was added with ethyl acetate and filtered by celite. The resulting solution was washed with 1N HCl(aq) and water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under a reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate=3/1 as an eluting solvent and dried under a reduced pressure to obtain 32.3 g of 1-chloro-6-(1-pentynyl)-2-naphthol (S7-3).
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[Cl:15][C:16]1[C:17]([F:26])=[C:18]([CH:22]=[CH:23][C:24]=1[F:25])C(O)=O.CN(C=O)C>C([O-])(O)=O.[Na+].CCOC(C)=O>[Cl:15][C:16]1[C:24]([F:25])=[C:23]([CH:22]=[CH:18][C:17]=1[F:26])[C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(F)c(Cl)c1F
Temperature: 80 °C

Procedure:
A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80° C. for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil.
Reaction SMILES: [C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])=[C:6]([CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]>[Pd].C(O)(=O)C>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]1[C:6]([CH2:18][CH3:19])=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:16]([OH:17])[CH:15]=1
Reactant: CCc1cc(C(C)=O)c(O)cc1OCCCCC#N
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1cc(C(C)=O)c(O)cc1OCCCCCN
Reaction time: 2 h

Procedure:
A mixture of 2.0 % of 5-(4-acetyl-2-ethyl-5hydroxyphenoxy)pentanenitrile, 50 ml of acetic acid, and 2.0 g of 10% palladium on carbon were subjected to hydrogenation for approximately 2 hours. The mixture was then filtered and concentrated in vacuo. The residue was triturated with diethyl ether to provide 2 g of the desired title product, m.p.=75°-76° C. NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][NH:13][CH2:12]1.[CH3:30]I>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=2)[C:15](=[O:29])[CH2:14][N:13]([CH3:30])[CH2:12]1
Reactant: COc1cccc(OC)c1C1CNCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: CI
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1CN(C)CC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A cooled (0° C.) solution of 6-(2,6-dimethoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)-piperazin-2-one (106 mg; 0.25 mmol) in anh. THF (1.5 ml) was treated with a solution of CH3I (33 mg; 0.23 mmol) in anh. THF (0.5 ml). The resulting mixture was allowed to warm-up slowly to rt, and stirring at rt was then continued for 15 h. Brine was added, and the mixture was extracted with AcOEt (3×20 ml). The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions D): tR=0.87 min.; [M+H]+: 425.02 g/mol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:22][CH2:21]1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:24][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: COc1ccccc1N1CCN(CCCCN)CC1
Product: COc1ccccc1N1CCN(CCCCNc2cc(Cl)ccc2[N+](=O)[O-])CC1

Procedure:
The compound was prepared according to the method described in Farmaco Ed. Sci. 36, 359 (1981) from 2,4-dichloronitrobenzene and 4-(2-methoxyphenyl)-1-piperazinbutanamine. M.p. 227°-229° C. as hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(=O)O[CH2:16][CH2:15][O:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:14][CH2:15][CH2:16][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: O=C1OCCO1
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Cl)c2cccnc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-8-hydroxyquinoline (1 mmol, 180 mg), ethylene carbonate (2 mmol, 180 mg) and Cs2CO3 (0.6 mmol, 195 mg) in dry DMF (10 mL) was stirred vigorously at 120° C. for 3 h. DMF was evaporated under high-vacuum and the residue was dissolved in water (15 mL), extracted twice with dichloromethane (15 mL), and the residue left after evaporation of dichloromethane was chromatographed over silica gel (eluent: 4:1 hexanes-EtOAc). A biege colored solid was obtained (174 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:11])=[C:6]([CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[CH:5]=[C:4]([C:32]2[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=2[O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[N:3]=1.C(N(CC)CC)C.Cl[C:52](Cl)([O:54]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:13]1([NH:12][C:10]([N:9]2[CH2:8][C:7]3[C:6]([CH:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)=[CH:5][C:4]([C:32]4[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][C:33]=4[O:39][CH2:40][CH:41]4[CH2:43][CH2:42]4)=[N:3][C:2]=3[NH:1][C:52]2=[O:54])=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNC(=O)NC2CCCCC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(C(=O)NC2CCCCC2)C(=O)N3)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-{2-amino-3-({[(cyclohexylamino)-carbonyl]amino}methyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (0.039 g, 0.065 mmol), which was obtained in the step (1) of Example 23-3, and triethylamine (15.0 mL, 0.389 mmol) in tetrahydrofuran (10.0 mL) was added dropwise a solution of triphosgene (0.019 g, 0.065 mmol) in tetrahydrofuran (5.0 mL) under an argon atmosphere. The mixture was stirred at 0° C. for 2 hrs. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (white solid) was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give tert-butyl 3-{3-[(cyclo-hexylamino)carbonyl]-7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl}-1-piperidinecarboxylate (0.021 g, yield; 52%).
Reaction SMILES: C1C([C:7]2[NH:23][C:21](=O)[C:9]3=[C:10](C4C=CC(Cl)=CC=4)[NH:11][C:12](=[O:13])[C:8]=23)=CC=C(Cl)C=1.S(=O)(=O)(O)[OH:26]>O>[O:26]=[C:8]1[C:7]2[C:10]([CH:9]=[CH:21][N:23]=2)=[N:11][C:12]1=[O:13]
Reactant: O=C1NC(c2ccc(Cl)cc2)=C2C(=O)NC(c3ccc(Cl)cc3)=C12
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=c1nc2ccnc-2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The pigment dispersant A1 of Synthesis Example A1 (3.75 parts) and C.I. Pigment Red 254 (6.25 parts) were added to 95% sulfuric acid (100 parts), followed by stirring at room temperature for 1 hour. Subsequent to cooling, the resulting concentrated sulfuric acid solution was poured into iced water (1,000 parts); its pouring led the precipitation of a composite according to the present invention. The formed precipitate was collected by filtration and then washed with water to obtain a water-based paste (39 parts, true amount: 10 parts). The water-based paste was dried to obtain a diketopyrrolopyrrole (a pigment dispersant A3, 10 parts), which was determined to contain on average 0.3 sulfonic group introduced per molecule from the results of an elemental analysis for sulfur.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:17]([O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)[CH2:18][CH3:19]>CCOC(C)=O>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH2:17][CH2:18][CH3:19])[CH:26]=3)[N:3]=2)[NH:8][CH:9]=1)=[O:16]
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: CCCOc1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Product: CCCOc1cccc(-c2cnc3[nH]cc(C(=O)C(C)(C)C)c3n2)c1

Procedure:
2,2-Dimethyl-1-[2-(3-propoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-propyloxybenzene boronic acid following general procedures as described in these Examples. Silica gel chromatography using 30-70% EtOAc in hexanes as eluant provided 56 mg (38%) of a yellow solid. MP 179-180° C., M+H=338.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].F[B-](F)(F)F.[O:25]=[N+:26]=[O:27]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:11]([N+:26]([O-:27])=[O:25])=[C:10]([F:12])[C:9]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(-c2c(C)noc2C)c(F)cc1N
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2c(C)noc2C)c(F)c([N+](=O)[O-])c1N

Procedure:
To a mixture of methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate (14 g, 53 mmol, 1 equiv.) and TFA (100 mL) is slowly added nitronium tetrafluoroborate (9.1 g, 68.9 mmol, 1.3 equiv.). After completion, the mixture was concentrated under reduced pressure. The residue was dissolved and then the residue was dissolved in EtOAc (200 ml) and washed with brine (30 ml×2). The organic solvent was evaporated. Methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-3-nitrobenzoate was used without further purification. 1H NMR (400 MHz, Chloroform-d) δ 6.92 (d, J=5.8 Hz, 1H), 4.24 (s, 4H), 4.07-3.85 (m, 5H), 2.46-2.34 (m, 4H), 2.31-2.22 (m, 5H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH:10]O>C(O)(=O)C>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[CH2:2][CH3:3]
Reactant: CCCc1ccccn1
Reactant: OO
Solvent: CC(=O)O
Product: CCCc1cccc[n+]1[O-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 2-n-propylpyridine (187.4 g, 1.505 mol) in 900 ml of acetic acid was added 149 ml of 35% aqueous hydrogen peroxide and the mixture was stirred and heated to 70-80° C. After three hours a further 104 ml of the hydrogen peroxide solution was added, and the mixture was maintained at the same temperature for an additional nine hours. The mixture was concentrated to about 300 ml in volume, 300 ml of water was added, and the mixture was concentrated as far as possible. The residue was made alkaline with anhydrous sodium carbonate, shaken with 750 ml of dichloromethane, and allowed to stand overnight. The resulting deposit of sodium carbonate and sodium acetate was removed by filtration. The filtrate was dried over magnesium sulfate, the solvent removed, and the residue distilled under reduced pressure. This gave 176 g (81%) of 2-n-propylpyridine-N-oxide. B.p. 120-140° C./9-15 mbar. 1H-NMR (CDCl3, 200 MHz) δ: 1.05 (t, 3H); 1.80 (sext, 2H); 2.89 (t, 2H); 7.10-7.28 (m, 3H); 8.28 (d, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[CH3:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:20]([O:24][C:25]([NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:10]2[C:11]([CH3:13])=[C:12]3[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:15])[CH2:29]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(C)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(C)c21
Yield: 52.8 %

Procedure:
A mixture of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (420 mg), 3-t-butoxycarbonylaminopyrrolidine (350 mg), DBU (260 mg) and anhydrous acetonitrile (10 ml) was refluxed for 35 hours. After the reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform (40 ml), washed with 10% aqueous citric acid solution and saturated aqueous sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from methanol to give 7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-1-ethyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-3-quinolinecarboxylic acid (360 mg) as white prisms, mp 184.5°-187.5° C. (decompd.).