Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@H:4]([C:9]([OH:11])=O)[CH2:5][CH2:6][S:7][CH3:8])=[O:2].ON1C2C=CC=CC=2N=N1.[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][SH:39])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1.C(N(CC)CC)C>C(OCC)(=O)C>[F:22][C@:23]12[C@@H:43]([OH:44])[CH2:42][C@@:41]3([CH3:45])[C@@H:33]([CH2:34][C@H:35]([CH3:47])[C@:36]3([OH:46])[C:37](=[O:40])[CH2:38][S:39][C:9](=[O:11])[CH:4]([NH:3][CH:1]=[O:2])[CH2:5][CH2:6][S:7][CH3:8])[C@@H:32]1[CH2:31][CH2:30][C:29]1[C@:24]2([CH3:49])[CH:25]=[CH:26][C:27](=[O:48])[CH:28]=1
Reactant: CSCC[C@H](NC=O)C(=O)O
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CS
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CSCCC(NC=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reaction time: 1.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of N-formyl-L-methionine (11.13 gm) in dry ethyl acetate (200 ml) were added 1-hydroxybenzotriazol (9.71 gm) in dry ethyl acetate (100 ml) and dicyclohexylcarbodiimido (16.43 gm) in dry ethyl acetate (100 ml) each at room temperature. The reaction mixture was stirred for 1.5 hours. To the stirred reaction mixture was added dropwise a solution of 9-fluoro-11β,17-dihydroxy-16β-methylpregna -1,4-diene-3,20-dione-21-thiol (12.95 gm) and triethylamine (35 ml) in dry ethyl acetate (600 ml) at 0° C. for 1 hour. The reaction mixture was stirred at room temperature for 4.5 hours. The title compound (15.68 gm) was prepared by purifying the resulting reaction mixture in the same manner as in Synthetic Example 1.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[N:11][CH:12]=1.Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Pd].C1(C)C=CC=CC=1.O1CCCC1>[Cl:13][C:10]1[N:11]=[CH:12][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccccc1
Reactant: Clc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2ccccc2)cn1
Temperature: 10 °C
Reaction time: 1.5 h
Yield: 68.6 %

Procedure:
In a 300 mL inner volume flask replaced by nitrogen, 30.3 g of tetrahydrofuran solution containing 19.5% by weight of isopropylmagnesium chloride (57.5 mmol as isopropylmagnesium chloride) as a magnesiation reagent was charged, and cooled at 10° C., and then 20 g of tetrahydrofuran solution containing 5-bromo-2-chloropyridine (9.6 g, 50.0 mmol) as a 2,5-dihalogenopyridine derivative (I), was added dropwise in the range of 10 to 20° C. for 1.0 hour. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 1.5 hours, and then added dropwise to the solution of tetrahydrofuran (20 g) containing bromobenzene (7.9 g, 50.0 mmol) as a halogenoaryl derivative (II), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.20 g, 0.25 mmol) as a palladium compound in the range of 10 to 20° C. for 2.0 hours. After adding dropwise, the reaction mixture was stirred in the range of 10 to 20° C. for 4.0 hours, and then saturated aqueous solution of ammonium chloride (50 g) was added. Toluene (50 g) was added to the reaction mixture, and after stirring for 1.0 hour, the reaction mixture was left to stand to separate the organic layer. After washing the organic layer with saturated sodium chloride solution (10 g), it was condensed under reduced pressure to obtain crude 6-chloro-3-phenylpyridine (6.5 g, purity: 82%, yield: 60%). The resultant crude 6-chloro-3-phenylpyridine (6.5 g) was purified by silica gel column chromatography (200 g), and 6-chloro-3-phenylpyridine (4.5 g, yield: 42%) as a 6-halogeno-3-arylpyridine derivative (III) was obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:50]1[N:55]=[C:54]([C:56]2([CH2:63][F:64])[NH:61][C:60](=[O:62])[CH2:59][O:58][CH2:57]2)[CH:53]=[CH:52][CH:51]=1.[Cl:65][C:66]1[CH:67]=[CH:68][C:69]([C:72]([NH2:74])=[O:73])=[N:70][CH:71]=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O>[F:64][CH2:63][C:56]1([C:54]2[N:55]=[C:50]([NH:74][C:72]([C:69]3[CH:68]=[CH:67][C:66]([Cl:65])=[CH:71][N:70]=3)=[O:73])[CH:51]=[CH:52][CH:53]=2)[CH2:57][O:58][CH2:59][C:60](=[O:62])[NH:61]1
Reactant: O=C1COCC(CF)(c2cccc(Br)n2)N1
Reactant: NC(=O)c1ccc(Cl)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: O=C1COCC(CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)n2)N1
Temperature: 80 °C

Procedure:
A mixture of 4,5-Bis(diphenyl phosphino)-9,9-dimethyl xanthene (0.04 g, 0.069 mmol), tris(dibenzylidene-acetone) di palladium(0) (0.032 g, 0.035 mmol) and cesium carbonate (0.678 g, 2.083 mmol) were taken in 1,4-dioxane and degassed with argon for 10 min. 5-(6-Bromo-pyridin-2-yl)-5-fluoromethyl-morpholin-3-one (0.2 g, 0.694 mmol) followed by 5-chloropicolinamide (0.119 g, 0.764 mmol) were added to the resultant reaction mixture and degassed with argon for further 5 min. Reaction mixture was then heated at 80° C. for 16 h and cooled to rt. Reaction contents were treated with water and product was extracted with ethyl acetate, washed with brine and dried over anhy. Na2SO4. The organic layer was concentrated under reduced pressure to obtain liquid which was triturated with n-pentane to furnish title compound as a off-white solid. Yield=0.24 g (crude). TLC (50% ethyl acetate in hexane) Rf=0.45; LCMS: RtH8=1.215, [M+1]=365.1 and 366.9; HPLC RtH9=4.367 min (53
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH2:14]>C1(C)C=CC=CC=1>[C:1]([CH2:3][C:4]([NH:14][CH2:13][CH2:12][CH2:11][N:10]([CH3:15])[CH3:9])=[O:6])#[N:2]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)CC#N
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)CC#N
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Ethyl cyanoacetate (51.106 g, 0.4518 mole) was added to 3-(dimethylamino) propylamine (46.162 g, 0.4518 mole) in a 250 ml round bottom flask equipped with a magnetic stir bar. After stirring for approximately 0.5 hr, 50 ml of toluene was added. The clear orange liquid was stirred at room temperature for approximately 15 hours, after which the ethanol and toluene were removed via vacuum distillation. 2-Cyano-N-[3-(dimethylamino)propyl]acetamide was obtained in 96% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2ccnc(O)c2c1
Product: Cc1ccc2ccnc(Cl)c2c1
Yield: 85 %

Procedure:
The solution of POCl3 (10 mL) and 7-methyl-isoquinolin-1-ol (3.55 g, 22.3 mmol) was refluxed under nitrogen for 5 h. The residue, after removal of POCl3 by distillation, was quenched with iced water and extracted with methylene chloride (3×). Purification by flash silica gel column using 10-25% EtOAc in hexane as elute gave 3.40 g (85% yield) of desired product. 1H-NMR (300 MHz, CDCl3) δ 8.21 (d, 1H), 8.11 (s, 1H), 7.75 (d, 1H 7.60 (d, 1H), 7.55 (d, 1H), 2.60 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH:16]=[O:17])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:18][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH:16]([OH:17])[CH3:18])=[C:11]([CH:13]([CH3:15])[CH3:14])[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Reaction time: 1 h
Yield: 40.8 %

Procedure:
A solution of 2-(4-bromo-phenyl)-4-isopropyl-oxazole-5-carbaldehyde (14.4 g, 84.9 mmol) in THF (300 mL) is cooled to −78° C. and treated dropwise with methyl magnesium bromide (25 mL, 75 mmol, 3M Et2O). After 1 h, more methyl magnesium bromide (12 mL, 36 mmol) is added. The reaction mixture is stirred 1.5 h, and saturated NH4Cl solution (10 ml) is added dropwise. The mixture is partitioned between saturated NH4Cl solution (10 ml), 1N HCl (25 mL), and Et2O (300 mL). The organic layer is washed with brine (150 mL), dried (Na2SO4), and concentrated. The crude product is purified by silica gel flash chromatography using hexanes:ethyl acetate (9:1 to 5:1) to give an offwhite solid (9.5 g, 63%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:10])[CH:8]=[O:9].[CH:11]1(C(=O)C(C)(C2C=CC=CC=2)CC=O)CCCCC1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH2:10][CH3:11])[CH:8]=[O:9]
Reactant: CC(CC=O)(C(=O)C1CCCCC1)c1ccccc1
Reactant: CC(C=O)c1ccccn1
Product: CCC(C=O)c1ccccn1

Procedure:
Scheme VI, steps A-D: 4-Cyclohexyl-3-methyl-4-oxo-3-(2-pyridylbutyraldehyde is prepared from 2-(2-pyridyl)-propanaldehyde in a manner analogous to the procedure described in example 7 for the preparation of 4-cyclohexyl-3-methyl-4-oxo-3-phenylbutyraldehyde.
Reaction SMILES: ClCCl.[CH2:4]([CH:7]1[O:12][CH:11](O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[C:22]([F:35])[C:21]=3[F:36])=[C:16]([F:37])[C:15]=2[F:38])[CH2:9][CH2:8]1)[CH2:5][CH3:6].C([SiH](CC)CC)C>O>[CH2:4]([CH:7]1[CH2:8][CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:27]4)=[C:22]([F:35])[C:21]=3[F:36])=[C:16]([F:37])[C:15]=2[F:38])[CH2:11][O:12]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4O)c(F)c3F)c(F)c2F)CC1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCC1CCC(c2ccc(-c3ccc(C4CCC(CCC)OC4)c(F)c3F)c(F)c2F)CC1
Reaction time: 3 h
Yield: 44.3 %

Procedure:
Dichloromethane (40 ml) was added to 6-propyl-3-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran-2-ol (17) (4.2 g) prepared in the second step. Triethylsilane (1.01 g) and a boron trifluoride-diethyl ether complex (1.82 g) were added dropwise to the solution at −30° C. After 3 hours of stirring, water (40 ml) was added to give two layers. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=80/20 by volume), and then by recrystallization (heptane/ethyl acetate=90/10 by volume) to give 2-propyl-5-(2,2′,3,3′-tetrafluoro-4′-(4-propylcyclohexyl)biphenyl-4-yl)tetrahydro-2H-pyran (18) (1.8 g) in 44.3% yield.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C:6]([C:9]([NH:11][CH2:12][CH:13]3[CH2:15][CH2:14]3)=[O:10])=[N:7][O:8][C:4]=2[CH:3]=1.[CH:18]1([NH:21][C:22](=[O:40])[C:23]2[CH:28]=[C:27](B3OC(C)(C)C(C)(C)O3)[C:26]([CH3:38])=[C:25]([F:39])[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(O)(C)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:18]1([NH:21][C:22]([C:23]2[CH:24]=[C:25]([F:39])[C:26]([CH3:38])=[C:27]([C:2]3[CH:17]=[CH:16][C:5]4[C:6]([C:9]([NH:11][CH2:12][CH:13]5[CH2:15][CH2:14]5)=[O:10])=[N:7][O:8][C:4]=4[CH:3]=3)[CH:28]=2)=[O:40])[CH2:20][CH2:19]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1noc2cc(Br)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(C(=O)NCC3CC3)noc2c1
Yield: 78.3 %

Procedure:
A mixture of 6-bromo-N-(cyclopropylmethyl)-1,2-benzisoxazole-3-carboxamide (Intermediate 56) (0.03 g) N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 62) (0.03 g) saturated aqueous sodium hydrogen carbonate (0.25 ml) and tetrakis(triphenylphosphine)palladium(0) (1 mg) in isopropanol (0.5 ml) was stirred at reflux under nitrogen for 4 h. Ethyl acetate (2 ml) and water (2 ml) were added, the phases were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic extracts were washed with brine, dried using a hydrophobic filter tube and concentrated under a stream of nitrogen. The residue was purified on Varian Bond-Elut SPE cartridge (silica, 1 g) eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound as a colourless foam (0.03 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 90.8 %

Procedure:
With 4.36 g of 3-bromo-4-methoxy toluene and 2.81 g of 5-chloroisatin as starting materials, 4.27 g of the title compound (light brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][O:60][C:61]1[N:66]=[CH:65][C:64]([CH2:67]O)=[CH:63][CH:62]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:67][C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(CO)cn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (6-methoxypyridin-3-yl)methanol (0.58 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.09 g, 81%).
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Yield: 96 %

Procedure:
50 parts of 2,5-dianilinoterephthalic acid are added with stirring at 125° C. to 225 parts of acid methyl polyphosphate (P2O5 content about 83%) in the course of 1 hour, and the mixture is stirred at said temperature for 2 hours. The cyclization melt is hydrolyzed by means of 300 parts of ice and 375 parts of water. The quinacridone formed is filtered off and is washed with water until neutral. The water-moist approximately 22% strength quinacridone is suspended in 400 parts of water. 18 parts of a 5% strength aqueous cetyltrimethylammonium chloride solution are added dropwise with stirring in the course of 10 minutes. After 30 minutes of stirring 75 parts of 10% strength potassium hydroxide solution are added, and the suspension is bulked to 750 parts with water. The suspension, possibly after a wet milling, is then stirred at 100° C. for 10 hours. It is then filtered and the filter cake is washed with water until neutral. The isolated water-moist approximately 18-22% strength quinacridone is suspended in 300 parts of 80% strength isobutanol, and the suspension is stirred at 145° C. in a sealed vessel for 5 hours. The isobutanol is separated off by steam distillation, and the bluish red pigment is isolated by filtration. The pigment obtained after drying in a yield of above 96% of theory produces when used in paint systems high-hiding, non-hazy, brilliant full-tone coatings of excellent gloss. The gloss value measured as described in Example 1 is 59.5.
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:27][OH:28].[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([CH2:12][C:13]2[N:17]3[N:18]=[C:19](/[C:22](=[N:27]/[OH:28])/[CH3:23])[CH:20]=[CH:21][C:16]3=[N:15][N:14]=2)=[C:10]([F:25])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: NO
Reactant: CC(=O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Yield: 92.8 %

Procedure:
1-[3-(5,7-Difluoro-quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]ethanone (78.4, 320 mg, 0.943 mmol) and hydroxylamine hydrochloride (131 mg, 1.886 mmol) in methanol (30 mL) was stirred at it overnight. LCMS showed the reaction was complete. The reaction solution was tuned with 1N NaOH aqueous solution until pH 8-9, solvent was evaporated, and the residue was purified by column chromatography to afford 310 mg (93% yield) of the title compound as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.29 (s, 1H), 8.99 (dd, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 7.74 (d, 2H), 7.63 (dd, 1H), 4.76 (s, 2H), 2.15 (s, 3H). LCMS (method A): [MH]+=355, tR=5.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C([Li])CCC.[CH3:16][O:17][CH2:18][N:19]=[C:20]=[S:21]>C1COCC1>[CH3:16][O:17][CH2:18][NH:19][C:20]([C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:8]=1)=[S:21]
Reactant: COCN=C=S
Reactant: Clc1ccnc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCNC(=S)c1cc2nccc(Cl)c2s1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
Solid 7-chloro-thieno[3,2-b]pyridine (60 g, 360 mmol) was added with stirring to 600 mL dry THF. Nitrogen was bubbled through the solution for ten minutes then cooled to −78° C. n-Butyl lithium (170 mL, 432 mmol) (2.5 M solution in hexanes) was added drop-wise at a rate such that the temperature is maintained below −65° C. The reaction mixture was stirred at −78° C. for three hours. Methoxymethyl isothiocyanate (43.2 mL, 468 mmol) in 400 mL THF was slowly added. Complete solution was noted after the addition was complete. The reaction mixture was then allowed to stir at −78° C. for three hours. The reaction mixture was removed from the cooling bath and 150 mL saturated NH4Cl solution was added. The reaction mixture turned a bright yellow color. THF was removed under reduced pressure, and 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid methoxymethyl amide was filtered, washed with ethyl acetate and dried giving 93.7 g, a 95% yield as a yellow-orange solid. C10H9ClN2OS2: APCI m/z 273.0/274.9 (MH+).); 1H NMR (d6-DMSO): δ 8.60 (d, 1H, J=5.0 Hz ), 8.13 (s, 1H), 7.55 (d, 1H, J=5.0 Hz ), 4.97 (s, 2H), 2.46 (s, 3H) ppm.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36]>CN(C=O)C>[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH:41][C:15](=[O:17])[CH2:14][CH2:13][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:10][CH:9]=1)=[O:18])[CH3:36]
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Yield: 449.2 %

Procedure:
An aliquot of 4-[[4(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (1.36 g) was added to dry DMF (50 ml) followed by N-methylmorpholine (0.6 mL) and isobutyl chloroformate (0.65 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for 5 min 0.45 g β-alanine ethyl ester hydrochloride was added followed by 0.6 mL of N-methyl morpholine. After 4 hr the solvent was removed under reduced pressure and the product was purified by reverse phase chromatography (water/acetonitrile) to give 4.4 g of white solid: 1H NMR (d6 -DMSO) δ 1.2 (t, 3H, J=7 Hz), 2.45 (m, 4H), 2.6 (m, 2H), 3.25 (m, 2H), 4.05 (q, 2H, J=7 Hz), 7.8 (s, 4H), 8.0 (m, 1H), 8.85 (bs, 2H), 9.18 (bs, 2H), 10.4 (s, 1H); MS (ES) m/e 335.1(M+H+).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:30])=[C:6]([CH:24]=[C:25]([N+:27]([O-])=O)[CH:26]=1)[NH:7][C:8]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2].[ClH:31]>C(O)C.[Pd]>[ClH:31].[C:1]([C:4]1[C:5]([OH:30])=[C:6]([CH:24]=[C:25]([NH2:27])[CH:26]=1)[NH:7][C:8]([C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[N:13]=[N:12][N:11]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2C(=O)Nc2cc([N+](=O)[O-])cc(C(C)=O)c2O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cc(N)cc(C(C)=O)c2O)cc1
Reaction time: 2.5 h

Procedure:
A solution of 3'-acetyl-2'-hydroxy-1-(4-methoxybenzyl)-5'-nitro-1H-tetrazole-5-carboxanilide (2.06 g) in a solution of hydrogen chloride in ethanol (0.36 N; 60 ml) was hydrogenated at atmospheric pressure and at 25° C., using a 5% w/w palladium on charcoal catalyst (0.5 g), during a period of 150 minutes. The catalyst was then filtered off and the filtrate was evaporated in vacuo. The resulting residue was recrystallised from ethanol to give 3'-acetyl-5'-amino-2'-hydroxy-1-(4-methoxybenzyl)-1H-tetrazole-5-carboxanilide hydrochloride (1.2 g), in the form of colourless crystals, m.p. 225° C. (with decomposition).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.ClCCl.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:29]4[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26][C:25]=4[CH:24]=[C:23]3[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccccn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 1-dram vial was added 273a (40 mg, 0.074 mmol), 2-aminopyridine, (1.2 equiv), cesium carbonate (1.5 equiv), Xantphos (10 mol %) and tris(dibenzylideneacetone) dipalladium(0) (5 mol %) in dry 1,4-dioxane (0.2 M). The reaction was then stirred at 80° C. for 3 hours. After cooling to room temperature, the reaction was then diluted with dichloromethane (3 mL) and washed with water (2×3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product 273b was then carried on to the subsequent step without purification.