Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[CH2:12][C:11]1([CH3:20])[CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:21][CH2:22][C:23]([CH2:27]O)([CH2:25][OH:26])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:21][CH2:22][C:23]1([CH3:27])[CH2:25][O:26][C:13]2([CH2:14][C:15]([CH3:17])([CH3:16])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:11]([CH3:19])([CH3:20])[CH2:12]2)[O:18][CH2:24]1
Reactant: CCCCCCCCON1C(C)(C)CC(=O)CC1(C)C
Reactant: CC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC2(CC1(C)C)OCC(C)(CO)CO2
Yield: 14.1 %

Procedure:
A mixture of 11.0 grams (38.5 mmol) of 1-octyloxy-2,2,6,6-tetramethylpiperidin-4-one, 10.2 grams (84.9 mmol) of 1,1,1-tris(hydroxymethyl)ethane, 1.4 grams of p-toluenesulfonic acid and 100 ml of toluene is heated at reflux for four hours. Water is collected in a Dean-Stark trap. Purification of the reaction mixture by flash chromatography on silica gel affords 2.1 grams (14% yield) of the title compound as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.O[CH2:29][C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:29][C:30]2[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=2)[O:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CCOC(=O)COc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(COc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Under nitrogen at 5° C., to a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (1.5 g), ethyl [3-(hydroxymethyl)phenoxy]acetate (885 mg) and triphenyl phosphine (1.1 g) in tetrahydrofuran (30 ml) was added diethyl azodicarboxylate (0.66 ml). The mixture was stirred at room temperature for 12 hours and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give ethyl [3-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]methyl]-phenoxy]acetate (1.04 g).
Reaction SMILES: [F:1][CH:2]([F:35])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH:23]([C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([O:33]C)=[O:32])[CH2:27][CH2:26]4)[CH3:24])=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1.[OH-].[Li+].Cl>C1COCC1.O.[Cl-].[Na+].O>[F:35][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH:23]([C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]4)[CH3:24])=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](C(C)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnc(C(C)[C@H]3CC[C@H](C(=O)O)CC3)nc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylate (isomer 1) (20 mg, 0.042 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide (3.0 mg, 0.12 mmol), and the mixture was stirred for 8 hours at 60° C. After cooling to room temperature, the mixture was adjusted to pH 2 by adding 1 M aqueous hydrochloric acid, diluted with brine, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give trans-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}cyclohexanecarboxylic acid, isomer 1 (example 6.1). MS ESI calc'd for C25H28F2N5O2 [M+H]+ 468. found 468. 1H NMR: (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.99 (s, 2H), 8.74-8.73 (m, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.24 (s, 1H), 7.10-7.09 (m, 1H), 6.91 (t, J=54 Hz, 1H), 2.84-2.80 (m, 1H), 2.37 (s, 3H), 2.13-2.07 (m, 1H), 1.96-1.81 (m, 3H), 1.73-1.71 (m, 1H), 1.36-1.06 (m, 8H).
Reaction SMILES: C(N(CC)[C:4]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1)C.[OH2:19]>COCCO>[C:11]1([C:8]2[CH:7]=[CH:6][NH:5][C:4](=[O:19])[CH2:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)C1=NC=CC(c2ccccc2)=CC1
Reactant: O
Solvent: COCCO
Product: O=C1CC=C(c2ccccc2)C=CN1

Procedure:
The crude diethyl-(5-phenyl-3H-azepin-2-yl)-amine (12.47 g) is added to water (10.0 mL) and 2-methoxy-ethanol (40.0 mL) and the resulting mixture heated to reflux and stirred 4½ days. The volatiles are removed in vacuo and the residue diluted with dichloromethane and washed with 0.1N HCl (2×200 mL) and saturated aqueous NaHCO3 (2×200 mL). The organic layer is dried over Na2SO4 and concentrated in vacuo to give the crude title compound as a dark brown solid (9.63 g). This material is carried into the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].[S].[CH2:13](N)[CH2:14][NH2:15]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:15][CH2:14][CH2:13][N:6]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C#N)cc1Br
Reactant: NCCN
Agent: [S]
Product: COc1ccc(C2=NCCN2)cc1Br
Temperature: 110 °C

Procedure:
To a solution of 3-bromo-4-methoxybenzonitrile (1 g, 4.72 mmol) in 10 mL of ethane-1,2-diamine was added sulfur (0.121 g, 3.77 mmol) and the mixture was heated at 110° C. overnight. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered, and concentrated to afford the title compound. LCMS: 257 (M+2)+.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCCC1>CO>[CH:11]1([CH:17]=[C:5]([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[C:6]([O:8][CH3:9])=[O:7])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1CCCCC1
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(=CC1CCCCC1)C(=O)C1CC1
Reaction time: 48 h
Yield: 74.6 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-oxopropanoate (3.00 g) and cyclohexanecarboxaldehyde (2.84 g) in MeOH (30 ml) was added piperidine (0.209 ml) at room temperature. The mixture was stirred for 48 h. The solvent was evaporated off, and the residue was chromatographed on a silicagel column chromatography (EtOAc-hexaens, a linear gradient of EtOAc from 0 to 15% over 60 min) afforded methyl 3-cyclohexyl-2-(cyclopropylcarbonyl)acrylate as a colorless oil (3.72 g).
Reaction SMILES: [OH-].[K+].FC(F)(F)C([N:7]1[CH2:15][C@@H:14]2[C@H:9]([CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[CH2:13]2)[CH2:8]1)=O>CO>[CH2:8]1[CH:9]2[CH:14]([CH2:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10]2)[CH2:15][NH:7]1
Reactant: O=C(N1C[C@H]2Cc3ccccc3C[C@@H]2C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)CC1CNCC1C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
To a stirred solution of potassium hydroxide (8.67 g, 154.6 mmol) in 100 mL of methanol was trans-2-trifluoroacetyl-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (8.32 g, 30.91 mmol), and the mixture was stirred at room temperature for four hours. The mixture was concentrated in-vacuo, and the residue was partitioned between diethyl ether and water. The layers were separated, and the aqueous phase was extracted with three 200 mL portions of diethyl ether. The combined organic phases were dried over sodium sulfate, and concentrated in-vacuo to a yellow oil. The oil was purified by flash chromatography on an 8×15 cm silica column, eluting with a 40:10:1 mixture of methylene chloride, methanol, and 25% aqueous ammonium hydroxide. Obtained 2.5 g of the trans isomer as a white solid, and 2.0 g of the cis isomer as a pale yellow solid. Yield=46% (trans), 37% (cis). NMR (trans) (300 MHz, CDCl3) δ 7.12 (m, 4H), 3.36-3.31 (m, 2H), 3.08-3.03 (m, 2H), 2.71-2.58 (m, 4H), 2.46 (bs, 1H), 1.90 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([S:10][CH3:11])[CH:4]=1.C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH2:20]([O:19][C:17]([C:16]1[C:15](=[O:14])[C:8]2[C:6](=[C:5]([S:10][CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[NH:7][CH:22]=1)=[O:18])[CH3:21]
Reactant: COc1ccc(N)c(SC)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c[nH]c2c(SC)cc(OC)cc2c1=O
Yield: 81.5 %

Procedure:
4-Methoxy-2-methylsulfenylaniline (1.5 g) and diethyl ethoxymethylenemalonate (1.9 g) were reacted in the same manner as in Experimental Example 1 to obtain 3-ethoxycarbonyl-6-methoxy-8-methylsulfenyl-4(1H)-quinolone (2.1 g). The compound (1.3 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6-methoxy-8-methylsulfenyl-4(1H)-quinolone (compound 30, 0.95 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([OH:28])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1.C(O)(=O)C.C(#N)C.O>[OH:28][C@@H:13]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@H](O)CNC(=O)OCc2ccccc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CN1CCN(C[C@H](O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
Tert-butyl 4-[(2R)-3-benzyloxycarbonylamino-2-hydroxy-propyl]piperazine-1-carboxylate 20c (1.80 g, 4.80 mmol) was dissolved in 30 mL of dichloromethane followed by the addition of 20 mL of a solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure, added with 30 mL of water and 30 mL of acetonitrile, formaldehyde (288 mg, 9.6 mmol) and dropwise with 0.1 mL of acetic acid. The resulting solution was stirred for 0.5 hours followed by the addition of sodium triacetoxyborohydride (3.05 g, 14.40 mmol). The reaction solution was stirred for 12 hours, added dropwise with saturated sodium carbonate solution to adjust pH to 10 and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl N-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]carbamate 20d (830 mg, yield: 56.0%) as a yellow oil.
Reaction SMILES: [CH3:1]/[C:2](/[CH:27]=[CH:28]/[CH:29]=[C:30](/[CH:32]=[CH:33]/[C@:34]12[C:40]([CH3:42])([CH3:41])[CH2:39][C@H:38](O)[CH2:37][C@@:35]1([CH3:44])O2)\[CH3:31])=[CH:3]\[CH:4]=[CH:5]\[CH:6]=[C:7](\[CH:9]=[CH:10]\[CH:11]=[C:12](\[CH:14]=[C:15]=[C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][C@H:19](O)[CH2:18][C@:17]1(O)[CH3:25])/[CH3:13])/[CH3:8].C/C(/C=C/C=C(\C)/C=C/[C@]12C(C)(C)C[C@H](O)C[C@@]1(C)O2)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@]12C(C)(C)C[C@H](O)C[C@@]1(C)O2>>[CH3:44][C:35]1[CH2:37][CH2:38][CH2:39][C:40]([CH3:41])([CH3:42])[C:34]=1/[CH:33]=[CH:32]/[C:30](/[CH3:31])=[CH:29]/[CH:28]=[CH:27]/[C:2](/[CH3:1])=[CH:3]/[CH:4]=[CH:5]/[CH:6]=[C:7](\[CH3:8])/[CH:9]=[CH:10]/[CH:11]=[C:12](\[CH3:13])/[CH:14]=[CH:15]/[C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:25]
Reactant: C/C(C=C=C1C(C)(C)C[C@H](O)C[C@@]1(C)O)=C\C=C\C(C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C
Agent: CC(/C=C/C=C(C)/C=C/[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C)=C\C=C\C=C(C)\C=C\C=C(C)\C=C\[C@@]12O[C@]1(C)C[C@@H](O)CC2(C)C
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)CCCC2(C)C)C(C)(C)CCC1

Procedure:
The Tagetes erecta plant or regenerable portion thereof according to claim 13 that further exhibits at least one of a neoxanthin plus violaxanthin ratio of about 1:5 to about 1:1, a β-carotene ratio of about 0.05 to about 0.9 for flower petals and about one for leaves, an α-cryptoxanthin ratio of about 0.25 to about 0.9, a phytoene ratio of about 0.3 to about 1 or a phytofluene ratio of about 0.2 to about 1, wherein the xanthophylls are assayed as alcohols.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].F[CH:29](F)[C:30](O)=O>>[CH2:29]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH3:30]
Reactant: O=C(O)C(F)F
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 79 %

Procedure:
Compound 125 was prepared according to General Method 6 (EXAMPLE 3) from (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (30 mg, 0.1 mmol) and NaBH4 pellets (large excess, >10 equiv) in 5 mL difluoroacetic acid (0.02 M) stirred at rt for 12 h, to afford 28 mg (79%) of (3R)-4-ethyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. 1H NMR (500 MHz, CDCl3) 7.44 (d, J=9.3, 1H), 7.30 (d, J=9.3, 1H), 7.21 (s, 1H), 5.98 (m, 1H), 5.49 (m, 1H), 4.55 (dd, J=10.7, 2.4, 1H), 3.84 (dd, J=10.7, 2.4, 1H), 3.79 (m, 1H), 3.54 (m, 1H), 2.93 (m, 1H), 1.84 (m, 1H), 1.39 (d, J=6.3, 3H), 1.38 (d, J=6.3, 3H), 1.00 (d, J=9.8, 3H), 0.99 (d, J=9.8, 3H). This material (13 mg, 0.03 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 3 mL acetic acid and 3 mL concentrated HCl heated at 90° C. for 4 h to afford 8 mg (70%) of Compound 125, after purification by column chromatography (3:1 hexanes: EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3) δ 11.59 (bs, 1H), 7.15 (d, J=8.8, 1H), 7.13 (s, 1H), 6.94 (d, J=8.8, 1H), 5.96 (m, 1H), 4.55 (dd, J=10.7, 1.3, 1H), 3.87 (dd, J=10.7, 2.4, 1H), 3.74 (m, 1H), 3.50 (m, 1H), 2.91 (bd, J=8.8, 1H), 1.80 (m, 1H), 1.00 (d, J=11.7, 3H), 0.97 (d, J=11.7, 3H).
Reaction SMILES: COC1C=C[C:6]([C:9]2[CH:10]=[C:11](C)[C:12](=O)[NH:13]N=2)=CC=1.BrCCCCl.[Cl:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:34]=[C:35]([CH3:41])[C:36](=[O:40])[N:37]([CH3:39])[N:38]=2)=[CH:29][CH:28]=1.N1CCCCC1>>[Cl:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:34]=[C:35]([CH3:41])[C:36](=[O:40])[N:37]([CH3:39])[N:38]=2)=[CH:31][CH:32]=1.[CH3:39][N:37]1[C:36](=[O:40])[C:35]([CH3:41])=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][N:13]3[CH2:6][CH2:9][CH2:10][CH2:11][CH2:12]3)=[CH:28][CH:29]=2)=[N:38]1
Reactant: COc1ccc(-c2cc(C)c(=O)[nH]n2)cc1
Agent: Cc1cc(-c2ccc(OCCCCl)cc2)nn(C)c1=O
Agent: ClCCCBr
Solvent: C1CCNCC1
Product: Cc1cc(-c2ccc(OCCCN3CCCCC3)cc2)nn(C)c1=O

Procedure:
6-(4-(3-Chloropropoxy)-phenyl)-2,4-dimethyl-2H-pyridazin-3-one was prepared from the product of step 3 and 3-bromo-1-chloropropane using the procedure described for Example 22 step 4. Example 39 (2,4-dimethyl-6-[4-(3-piperidin-1-yl-propoxy)-phenyl]-2H-pyridazin-3-one) was prepared using 6-(4-(3-chloropropoxy)-phenyl)-2,4-dimethyl-2H-pyridazin-3-one and piperidine by the methods described for example 22 step 5. The hydrochloride salt was prepared; Mp 222-3° C.; MS m/z 342 (M+H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([N+:15]([O-])=O)[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:14])([F:13])[F:12].[H][H]>CO.[Ni]>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:12])([F:13])[F:14])[NH2:15]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc(OC(F)(F)F)c(OC(F)(F)F)c1
Yield: 92.7 %

Procedure:
291 g of the 3,4-bistrifluoromethoxynitrobenzene thus obtained were hydrogenated with 20 bar of hydrogen in the course of 3 hours at 40° C. in 500 ml of methanol with the addition of 10 g of Raney nickel. After filtering off the catalyst with suction, the filtrate was fractionally distilled and 242 g of 3,4-bistrifluoromethoxyaniline were obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](CC)=NC=C([CH:11]=1)C(O)=O)C.C([O:18][C:19](=[O:29])[C:20]1[CH:25]=[C:24](Cl)[C:23]([CH:27]=[CH2:28])=[N:22][CH:21]=1)(C)(C)C>>[CH2:27]([C:23]1[C:24]([CH2:1][CH:3]([CH3:4])[CH3:11])=[CH:25][C:20]([C:19]([OH:18])=[O:29])=[CH:21][N:22]=1)[CH3:28]
Reactant: CCc1cc(C(=O)O)cnc1CC
Reactant: C=Cc1ncc(C(=O)OC(C)(C)C)cc1Cl
Product: CCc1ncc(C(=O)O)cc1CC(C)C

Procedure:
6-Ethyl-5-isobutyl-nicotinic acid is prepared in analogy to 5,6-diethyl-nicotinic acid from 5-chloro-6-vinyl-nicotinic acid tert.-butyl ester and 2,4,6-tri-(2-methyl-propenyl)-cycloboroxane pyridine complex (prepared in analogy to a procedure given by F. Kerins, D. F. O'Shea, J. Org. Chem. 67 (2002) 4968-4971); LC-MS: tR=0.64 min, [M+1]+=207.98.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[N:15][C:14]([NH2:17])=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([NH:17][C:14]2[N:15]=[CH:16][C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)=[N:20][CH:21]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Nc1ncc(-c2cccnc2)c2cccnc12
Product: Fc1ccc(Nc2ncc(-c3cccnc3)c3cccnc23)nc1

Procedure:
The title compound, MS: m/e=318.1 (M+H+), was prepared in accordance with the general method of example 6 step 3 from 5-pyridin-3-yl-[1,7]naphthyridin-8-ylamine and 2-bromo-5-fluoro-pyridine (Example C).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([O:19]C)[CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:29].ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(O)C=2)CCC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH:12]=[CH:11][C:10]1=[O:29]
Reactant: COc1cc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Agent: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Product: O=c1ccc2c(-c3ccc(F)cc3F)cc(O)cc2n1-c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-7-hydroxy-2(1H)-quinolinone was prepared from 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 4) by a procedure analogous to that described in INTERMEDIATE 3. Mass spectrum (ESI) 418.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.57 (d, J=8 Hz, 1H); 7.47 (d, J=7.5 Hz, 2H); 7.33 (m, 2H); 7.02 (m, 2H); 6.96 (s, 1H); 6.52 (d, J=9.5, 1H); 6.01 (s, 1H).
Reaction SMILES: C(OC(=O)C1C=CC(NC(=O)C(N2C3C=C(F)C(F)=CC=3N=C2C2C=CC(Cl)=CC=2)C2CCCCC2)=CC=1)C.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[N:51]([CH:52]([CH:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[C:53](O)=[O:54])[C:50]3[CH:62]=[C:63]([F:67])[C:64]([F:66])=[CH:65][C:49]=3[N:48]=2)=[CH:43][CH:42]=1.[CH3:68][O:69][C:70](=[O:81])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH2:78])=[C:73]([C:79]#[N:80])[CH:72]=1>>[CH3:68][O:69][C:70](=[O:81])[C:71]1[CH:76]=[C:75]([F:77])[C:74]([NH:78][C:53](=[O:54])[CH:52]([N:51]2[C:50]3[CH:62]=[C:63]([F:67])[C:64]([F:66])=[CH:65][C:49]=3[N:48]=[C:47]2[C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=2)[CH:56]2[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61]2)=[C:73]([C:79]#[N:80])[CH:72]=1
Reactant: COC(=O)c1cc(F)c(N)c(C#N)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Product: COC(=O)c1cc(F)c(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C#N)c1

Procedure:
The title compound was prepared in analogy to example 22, intermediate d), from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-cyano-5-fluoro-benzoic acid methyl ester (Arzneimittel Forschung, 34(II), Nr. 11a, 1984; 1612-1624) to give the product as a light brown solid (20%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[N:30]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC.C(OCC)(=O)C.O>[Cl:35][C:31]1[N:30]=[C:29]([CH2:28][O:1][C:2]2[CH:3]=[C:4]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:5]=[C:6]3[C:10]=2[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]3)[CH:34]=[CH:33][CH:32]=1
Reactant: Clc1cccc(CBr)n1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3cccc(Cl)n3)c2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
A mixture of ethyl 7-hydroxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (1.39 g), 2-(bromomethyl)-6-chloropyridine (840 mg), potassium carbonate (1.02 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2.5 hr. Water was added to the reaction mixture, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=10:90-65:35, volume ratio), and the obtained solid was washed with diethyl ether to give the title compound (1.0 g, yield 54%) as white crystals. MS 501 (MH+).