Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.C(=O)(O)[O-].[K+]>CC(C)=O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc2ccccc2c1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2ccccc2c1OCC(F)(F)F

Procedure:
A mixture containing 20.2 g. (0.1 mole) of methyl 1-hydroxy-2-naphthoate, 29 g. (0.125 mole) of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 20 g. (0.2 mole) of anhydrous potassium bicarbonate and 200 ml. of dry acetone is refluxed for three days. Acetone is removed by distillation (steam bath). The residue is cooled and diluted with water. The resulting white solid is collected by filtration and washed successively with cold dilute sodium hydroxide solution and water. The solid is further purified by several rcrystallizations from aqueous alcohol followed by sublimation, (oil bath, 60°-75°/0.2 mm. Hg.) to give white solid, m.p. 69.5°-70.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20]OC)=[C:7]([CH:18]=1)[CH:8]=[N:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17].COC1C=CC(OC)=CC=1C=O>>[CH3:20][O:19][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][C:7]=1[CH:8]=[N:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17]
Reactant: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Agent: COc1ccc(OC)c(C=O)c1
Product: COc1ccc(OC)c(C=Nc2c(C)cccc2O)c1

Procedure:
2-[(2,5-dimethoxybenzylidene)amino]-3-methylphenol (F7) was prepared in a similar manner for the preparation of 2-[(5-Methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) by using 2,5-dimethoxybenzaldehyde (3.32 g, 20 mmol) instead of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) in 82% (4.44 g): 1H-NMR (400 MHz, CDCl3) δ2.32 (s, 3H), 3.84 (s, 6H), 6.77 (d, 1H, J=7.6 Hz), 6.82 (d, 1H, J=2.0 Hz), 6.83 (d, 1H, J=7.6 Hz), 6.91 (d, 1H, J=9.2 Hz), 6.99 (t, 1H, J=7.6 Hz), 7.06 (dd 1H, J=9.2, 2.0 Hz), 7.69 (s, 1H), 8.94 (s, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:17][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][CH:14]=1)[CH:7]=[CH:6]2.Br>C(O)(=O)C>[C:18]1([C:16]2[O:17][C:13]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]4)=[CH:14][N:15]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc2cc(-c3cnc(-c4ccccc4)o3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3cnc(-c4ccccc4)o3)ccc2c1
Yield: 96.2 %

Procedure:
A suspension of 5-(6-methoxy-2-naphthyl)-2-phenyl-1,3-oxazole (433 mg, 1.44 mmol), prepared in the previous step, in 20 mL of glacial acetic acid plus 12 mL of 48% aqueous HBr was stirred under nitrogen at 120° C. for 3 h. The volatiles were removed under reduced pressure. The residue was taken up in 10% methanol in methylene chloride and then made basic by the addition of an excess of 5% NaHCO3. The layers were separated and the aqueous layer extracted three times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give 6-(2-phenyl-1,3-oxazol-5-yl)-2-naphthol (398 mg, 96%) as a light brown solid, mp 235-238° C. Elemental Analysis for C19H13NO2: Calc'd: C, 79.43; H, 4.56; N, 4.87. Found: C, 78.39; H, 4.76; N, 4.71.
Reaction SMILES: [F-].[K+].CNCCNC.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[CH3:17]/[C:18](/[O:24][Si](C)(C)C)=[N:19]\[Si](C)(C)C>[Cu]I.C1(C)C=CC=CC=1>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:19][C:18](=[O:24])[CH3:17]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: CNCCNC
Agent: [F-]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccccc1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 51.8 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), KF (350 mg, 6.0 mmol), evacuated, backfilled with Ar. N,N′-Dimethylethylenediamine (11 μL, 0.10 mmol, 10 mol %), 2-iodotoluene (128 μL, 1.01 mmol), N,O-bis(trimethylsilyl)acetamide (300 μL, 1.21 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 16 h. The resulting suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with ethyl acetate (20 mL). The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 1:4; 15 mL fractions). Fractions 10-17 provided 78 mg (52% yield) of N-(2-methylphenyl)acetamide as white needles.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[CH:14]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OCC)cc3)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)O)cc3)no2)cc1
Temperature: 0 °C
Yield: 98.9 %

Procedure:
To a solution of Ethyl 4-[5-(4-n-pentyloxyphenyl)-isoxazol-3-yl]benzoate (6.33 g) in ethanol (60 ml) and tetrahydrofuran (90 ml) was added 2N sodium hydroxide aqueous solution (12.5 ml) at 80° C. The mixture was refluxed for 1 hour and poured into ice-water. The suspension was adjusted to pH 2.0 with 1N HCl. The precipitate was collected by filtration, washed with water and dried to give 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (5.80 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[NH:31][C:30]([CH3:35])=[CH:29]4)[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[CH3:35][C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][C:26]([NH:25][C:22]1[CH:21]=[CH:20][N:19]=[C:18]3[CH:17]=[C:16]([C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:15])[S:24][C:23]=13)=[CH:34][CH:33]=2
Reactant: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)sc34)ccc2[nH]1
Agent: Cl
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CCNCC5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared by treating 4-[7-(2-methyl-1H-indol-5-ylamino)-thieno[3,2-b]pyridine-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester with HCl gas as described in Example 64B. MS: 392 (MH+); HPLC Rf: 3.51 min.; HPLC purity: 93%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@@H:5]([CH3:34])[CH2:6][CH:7]([NH:22][C:23]([NH:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:11][CH:10]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH3:34])[CH2:6][C@H:7]([NH:22][C:23]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)[C@@H](C)CC(Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)NCC(=O)O

Procedure:
Next, a solution of (S)-4-(3-tert-butoxycarbonylmethyl-ureido)-5-(3′-chloro-biphenyl-4-yl)-2-methyl-pentanoic acid ethyl ester (261 mg, 59.1 mmol) in 8 mL of methylene chloride/TFA (1:1) is stirred at room temperature for 1 hour. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC using a gradient of 10% MeCN/water to 100% MeCN (0.1% TFA) and the product is further purified by chiral HPLC on a Chirapak OD-H column using heptane/ethanol (90:10) (0.1% TFA) to elute the title compound; HPLC Retention time 1.48 minutes (condition C): MS 447.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.03-1.05 (d, J=7.07 Hz, 3H), 1.08-1.12 (t, J=7.33 Hz, 3H), 1.27-1.34 (m, 1H), 1.70-1.76 (m, 1H), 2.62-2.67 (m, 1H), 2.71-2.76 (m, 2H), 3.66-3.68 (d, J=5.81 Hz, 2H), 3.71-3.78 (m, 1H), 3.95-4.00 (q, J=7.07 Hz, 14.40 Hz, 2H), 5.94-5.97 (t, J=5.56 Hz, 1H), 6.07-6.09 (d, J=8.34 Hz, 1H), 7.25-7.28 (m, 2H), 7.38-7.41 (m, 1H), 7.45-7.49 (t, J=7.83 Hz, 1H), 7.60-7.63 (m, 3H), 7.69-7.70 (t, J=1.77 Hz, 1H), 12.42 (s, 1H).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.O[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[N:24][C:23]([NH:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]4[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=3)=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1)=[O:11]
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(-c2cnc(NCc3ccc4ccccc4c3)cn2)cc1)C(=O)OCCN1CCOCC1
Reaction time: 8 h
Yield: 4.3 %

Procedure:
(S)-2-(Tert-butoxycarbonylamino)-3-(4-(5-(naphthalen-2-ylmethylamino)pyrazin-2-yl)phenyl)propanoic acid (48 mg, 0.090 mmol), 4-(2-hydroxyethyl)morpholine (12 mg, 0.090 mmol), triethylamine (18 mg, 0.180 mmol), and benzotriazole-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 18 mg, 0.090 mmol), in dichloromethane (3.0 ml) were stirred at room temperature for 5 hours. Additional triethylamine (18 mg, 0.180 mmol) and BOP (18 mg, 0.090 mmol) were added, and the mixture was stirred overnight. The mixture was concentrated and purified via prep HPLC to give 2 mg of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:16]([O:18][N:19]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])[CH3:17]
Reactant: CCON
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.94 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.47 g of O-ethylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.92 g of methyl (1R)-trans-3-[(E)-3-ethoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ON1C2C=CC=CC=2N=N1.ClC1C=CC([O:30][C:31](=O)[CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=C(Cl)C=1Cl.C(N1CCOCC1)C>CN(C)C=O>[CH2:37]([O:36][C:34]([NH:33][CH2:32][C:31]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:30])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccc(Cl)c(Cl)c1Cl
Agent: CCN1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16.5 g of phenylalanine are suspended in 150 ml of dimethylformamide (DMF), 13.5 g of 1-hydroxybenzotriazole, 38.8 g of benzyloxycarbonylglycine-trichlorophenyl ester and 12.8 ml of N-ethylmorpholine are added and the batch is stirred for 8 hours at room temperature. The product is concentrated in vacuo, dissolved in 1 liter of ethyl acetate and submitted to repeated extractions with200ml portions of 2 N citric acid and of saturated sodium chloride solution, respectively. The organic phase is dried over sodium sulfate and concentrated in vacuo. The residue crystallizes from ethyl acetate/diisopropyl ether.
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1.[OH-].[Na+].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32]>CN(C)C=O>[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#[N:32])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 20.8 %

Procedure:
To a methanol (6.3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (100 mg, 0.36 mmol) described in Manufacturing Example 18-1-1 was added a 2 N sodium hydroxide aqueous solution (180 μL, 0.36 mmol). This mixture was concentrated under a reduced pressure. N,N-dimethylformamide (1.3 mL) and 3-bromomethyl-benzonitrile (58 mg, 0.29 mmol) were added to the residue, which was stirred for 15 minutes at 60° C. This reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (24 mg, 17%).
Reaction SMILES: C(O)(C(F)(F)F)=O.COC1C=CC([CH2:14][N:15](C)[C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[C:21]([C:30]4[CH:35]=[C:34]([NH2:36])[C:33]([F:37])=[CH:32][C:31]=4[Cl:38])[C:22](=[O:29])[N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:18][N:17]=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O>[NH2:36][C:34]1[C:33]([F:37])=[CH:32][C:31]([Cl:38])=[C:30]([C:21]2[C:22](=[O:29])[N:23]([CH:26]([CH3:27])[CH3:28])[C:24]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:15][CH3:14])[CH:25]=3)[CH:35]=1
Reactant: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2Cl)c(=O)n3C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNc1cc2c(cn1)cc(-c1cc(N)c(F)cc1Cl)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.9 %

Procedure:
TFA (5.55 g, 48.7 mmol) was added to 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-1,6-naphthyridin-2(1H)-one (0.78 g, 1.62 mmol) and the reaction was stirred for 90 min at RT. Water (50 mL) was added and the reaction mixture was carefully treated with solid Na2CO3 until it was faintly basic. The solution was extracted with EtOAc (2×), and the combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography (MeOH/DCM) to afford 3-(5-amino-2-chloro-4-fluorophenyl)-1-isopropyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.42 g, 72% yield) as a white amorphous solid. 1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.60 (s, 1H), 7.17 (d, J=11.2 Hz, 1H), 6.95 (q, J=4.8 Hz, 1H), 6.71 (d, J=9.6 Hz, 1H), 6.41 (s, 1H), 5.30 (s, 2H), 5.08 (br s, 1H), 2.84 (d, J=4.8 Hz, 3H), 1.49 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 361.0 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C(Cl)(Cl)Cl>[C:27]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:20]3[C:15]4=[C:16]([C:21]5[CH:22]=[C:23]([C:37]([C:38]6[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=6)=[O:44])[CH:24]=[CH:25][C:26]=5[N:14]4[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=4)[CH:17]=[CH:18][CH:19]=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(C2(c3ccccc3)c3ccccc3-n3c4ccccc4c4cccc2c43)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
A degassed solution of 6.1 g (18 mmol) of 8,8-diphenyl-8H-indolo-[3,2,1-de]acridine in 40 ml of chloroform is cooled to 0° C., and 5 g (37 mmol) of AlCl3 are added. 3.9 g of benzoyl chloride are then added dropwise at this temperature, and the mixture is stirred for 8 h. 50 ml of water are added to the mixture, and the organic phase is separated off, filtered through silica gel and evaporated to dryness. The residue is recrystallised from toluene and from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 13.7 g (27 mmol), corresponding to 90% of theory.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].P(Br)(Br)[Br:13]>>[Br:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: BrP(Br)Br
Reactant: COC(=O)CCC/C=C\CO
Product: COC(=O)CCC/C=C\CBr

Procedure:
To 23.7 g of cis-7-hydroxy-5-heptenoic acid, methyl ester and 150 ml of hexanes under nitrogen at 0° C. was added dropwise, 7.05 ml of phosphorous tribromide. After 2 hours the reaction was quenched with ice, diluted with hexanes, washed once with water and once with saturated aqueous bicarbonate, dried and stripped at reduced pressure. The crude product was dissolved in ether and filtered through a plug of silica gel. Removal of the ether at reduced pressure gave 31.4 g of the desired compound. NMR: 5.95-5.35 ppm (2H, m, olefins), 3.95 ppm (2H, d, 7 Hz, BrCH2), 3.65 ppm (3H, s, OMe), 2.45-2.05 ppm (4H, m, CH2 --CH2), 1.8 ppm (2H, q, 7 Hz, CH2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[CH:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=[C:11]([C:20]#[N:21])[C:10]=2[CH:9]=[N:8]1>N.[Ni]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[C:11]([CH2:20][NH2:21])[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=2)[CH:9]=[N:8]1
Reactant: N#Cc1cc(C(F)(F)F)cc2c1cnn2C1CCCCO1
Agent: [Ni]
Agent: N
Product: NCc1cc(C(F)(F)F)cc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
To a solution of 1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole-4-carbonitrile (440 mg, 1.49 mmol) in ammonia (2M solution in methanol, 10 mL) was added Raney-Ni (1.27 g, suspension in water). The mixture was stirred under a hydrogen atmosphere (1 atm.) at RT for 16 h and then filtered. The filtrate was concentrated in vacuo to afford crude (1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazol-4-yl)methanamine (127, 267 mg, yield: 60%). MS (ESI) m/z: 300.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[C:13](O)(=O)CC(O)=O.Cl.O>C(N(CC)CC)C>[C:5]([C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[C:3]=1[C:8]([OH:7])=[O:9])(=[O:6])[CH3:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2c(F)cccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccc(F)c1C(=O)O

Procedure:
9 g of 3-fluorophthalic anhydride and 6.8 g of malonic acid are mixed in 80 ml of triethylamine and heated in an oil bath at 71-72° until evolution of gas ceases. The reaction mixture is mixed with 50 ml of 10% HCl/H2O and extracted with ether. The ether is evaporated off and the resulting black oil chromatographed on a column using 1 l of 20% of ethylacetate/hexane followed by 1 l of 30% ethylacetate/hexane to yield first the 3fluoro-isomer followed by the desired 6-fluoro isomer; m.p. 76-81.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)=[CH:7][C:4]=1[CH:5]=O.[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)=[CH:7][C:4]=1/[CH:5]=[CH:19]/[C:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:20]
Reactant: COc1cc(OC)c(-c2cn[nH]c2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cn[nH]c2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-(1H-pyrazol-4-yl)-benzaldehyde (Ex-74B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3 including an acid work-up. Yellow solid, mp>250° C. 1H-NMR (DMSO-d6) δ 12.42 (bs, 1H), 8.20–8.03 (m, 8H), 7.85 (d, J=16.1 Hz), 6.74 (s, 1H), 3.95 (s, 3H), 3.94 (s, 3H). MS m/z=379 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:19](=[O:21])[CH3:20])[C:12]([OH:18])=[CH:13][CH:14]=2)[CH:9]=1.[H-].[Na+].[Br:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br>CN(C)C=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([C:19](=[O:21])[CH3:20])[C:12]([O:18][CH2:30][CH2:29][O:28][CH2:27][CH2:26][Br:25])=[CH:13][CH:14]=2)[CH:9]=1
Reactant: BrCCOCCBr
Reactant: COC(=O)CCCOc1ccc2ccc(O)c(C(C)=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc2ccc(OCCOCCBr)c(C(C)=O)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.4 %

Procedure:
Under an argon atmosphere, 2 g (0.007 mol) of 4-[(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]-butanoic acid methyl ester in 5 ml of anhydrous dimethylformamide was added to a suspension of 0.29 g of sodium hydride in 25 ml of anhydrous dimethylformamide. The mixture was stirred at room temperature for 20 minutes and then 7.7 g of bis-(2-bromoethyl)ether was added and the mixture was stirred at room temperature for 20 hours. The solvent was removed and residual oil was purified by high pressure liquid chromatography using 25% ethyl acetate-hexane to yield 1.6 g (54%) of 4-[[8-acetyl-7-[2-(2-bromoethoxy)ethoxy]-2-naphthalenyl]oxy]butanoic acid methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.O1CCOCC1.[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1>O.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].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[B:30]1[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A screw-cap vial was charged with 66.15D (2.08 g, 5.39 mmol), 1,4-dioxane (20 mL), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) DCM adduct (available from Strem) (0.220 g, 0.269 mmol). The suspension was sparged with N2, and to it were added TEA (2.25 mL, 16.2 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (available from Aldrich) (1.17 mL, 8.08 mmol). The resulting mixture was stirred overnight at 100° C. (sealed vial), cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, 1 N HCl, and brine, dried (MgSO4), and concentrated. The crude product was twice purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 66.56A (1.09 g, 52% yield) as a crystalline white solid.