Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1(/[CH:25]=[C:26](\B2OC(C)(C)C(C)(C)O2)/[CH2:27][OH:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.[F-].[Cs+].C1COCC1>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH:20]1(/[CH:25]=[C:26](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:27][OH:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)OB(/C(=C\C2CCCC2)CO)OC1(C)C
Reactant: O=S(=O)(NCCc1ccccn1)c1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1ccccn1)c1ccc(/C(=C\C2CCCC2)CO)cc1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
Heat a suspension of 4-bromo-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (1.67 g, 4.89 mmol), (E)-3-cyclopentyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.60 g, 6.36 mmol), caesium fluoride (2.23 g, 14.7 mmol) and tetrakis(triphenylphosphino)palladium(0) (565 mg, 489 μmol) in 50 mL dioxane to reflux for 2 d and cool to r.t. thereafter. After addition of 50 mL THF filtrate the resulting suspension, wash with dichloromethane and concentrate under reduced pressure. Further purify the resulting brown oil by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to afford (E)-4-(2-cyclopentyl-1-hydroxymethyl-vinyl)-N-(2-pyridin-2-yl-ethyl)-benzenesulfonamide (929 mg) as a pale yellow oil. MS (m/e): 387 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH:14](OCC)=[O:15]>C(O)C.C1(C)C=CC=CC=1>[OH:15][CH:14]=[C:7]1[CH2:8][CH2:9][C:10]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[C:6]1=[O:11]
Reactant: CCOC=O
Reactant: Cn1ncc2c1CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1ncc2c1CCC(=CO)C2=O

Procedure:
A stirred mixture 16.8 grams of 1,5,6,7-tetrahydro-1-methyl-4H-indazol-4-one, 6 grams of 97% sodium hydride, 15 ml of ethyl formate, 3 drops of ethanol and 200 ml of toluene was heated at reflux for 16 hours. The mixture was then cooled and extracted twice with water and the aqueous extracts were combined and washed with ethyl ether. The aqueous solution was acidified with 5 N hydrochloric acid to a pH of approximately 4 and the resultant slurry was extracted several times with dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure to leave a residual dark oil. The oil was triturated with a 50:50 mixture of hexane and ethyl ether to give 1,5,6,7-tetrahydro-5-hydroxymethylene-1-methyl-4H-indazol-4-one melting at about 93°-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:30][C:27]3[N:26]=[CH:25][C:24]([C:23]([F:32])([F:22])[F:31])=[CH:29][N:28]=3)=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ncc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Br)c(F)c2)C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C(F)(F)F)cn3)c(F)c2)C1
Temperature: 120 °C
Yield: 46.8 %

Procedure:
To a 20 ml glass vial was added (RS)-2-(4-bromo-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (200 mg, example 96(e)) and 5-trifluoromethyl-pyrimidin-2-ylamine (145 mg, CAS 69034-08-8) in dioxane (5 ml). The reaction mixture was purged with argon for 5 min. 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (38.9 mg), tris(dibenzylideneacetone)dipalladium(0) (20.3 mg) and sodium tert-butoxide (59.9 mg) were then added. The vial was capped and heated at 120° C. for 16 h. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 50% EtOAc in heptane) to afford (RS)-2-[3-fluoro-4-(5-trifluoromethyl-pyrimidin-2-ylamino)-phenyl]-morpholine-4-carboxylic acid tert-butyl ester (115 mg, 47%) as a yellow gum. MS (ISP): 441.4 ([M−H]−).
Reaction SMILES: C1(C(N2CCNCC2)=O)CCCCC1.Cl[C:16]1[N:25]=[C:24](N)[C:23]2[C:18](=[CH:19][C:20]([O:29][CH3:30])=[C:21]([O:27][CH3:28])[CH:22]=2)[N:17]=1>>[CH3:28][O:27][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:29][CH3:30])[N:17]=[CH:16][N:25]=[CH:24]2
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: O=C(C1CCCCC1)N1CCNCC1
Product: COc1cc2cncnc2cc1OC

Procedure:
N-(Cyclohexylcarbonyl)piperazine (5.9 g., 0.03 mole) and 2-chloro-4-amino-6,7-dimethoxyquinazoline (7.2 g., 0.03 mole) are reacted according to the procedure of Example 127(a). The crude product crystallized from methanol affords analytically pure 4-amino-2-4-(cyclohexylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline, m.p. 223°-225° C., resolidifying and remelting at 248.0°-250.0° C. (corr.)
Reaction SMILES: [C:1]([O:20]CC(CO)O)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C([O-])(=O)CCCCCCCCCCCCCCCCC>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: CCCCCCCCCCCCCCCCCC(=O)O

Procedure:
Cetearyl Alcohol (32%); Glyceryl Stearate (21%); Peg-100 Stearate (10%); Sodium Polyacrylate (5%)
Reaction SMILES: Cl[CH:2]([CH:28]([CH3:30])[CH3:29])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:27])[CH2:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:19])=O>CN(C)C1C=CN=CC=1.O1CCCC1.O.CC(C)=O>[CH3:30][CH:28]([CH:2]1[C:3]2=[N:5][C:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][CH:9]=[CH:8][C:7]=3[C:16]([OH:27])=[C:17]2[C:18](=[N:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[O:19]1)[CH3:29]
Reactant: CC(C)C(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)C1OC(=Nc2ccccn2)c2c1nc1c(C(F)(F)F)cccc1c2O
Yield: 84.7 %

Procedure:
10.5 g of the product of Step A and 2.9 g of 4-dimethylamino-pyridine in 100 ml of tetrahydrofuran were refluxed for 7 hours 30 minutes and after cooling, the solvent was eliminated under reduced pressure. The residue was taken up in 100 ml of water and 10 ml of acetone. After separating, washing with water and drying at 70° C. under reduced pressure, 7.8 g of 1,3-dihydro-3-(1-methylethyl)-1-[(2-pyridinyl)-imino]-5-trifluoromethyl furo-[3,4-b]-quinolin-9-ol melting at 178°-180° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([OH:12])=[O:11])[NH:4][N:3]=1.Cl.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([C:10]([O:12][CH2:19][CH3:20])=[O:11])[NH:4][N:3]=1
Reactant: CCO
Reactant: Cc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1[nH]nc(C)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 3-methyl-4-nitropyrazole-5-carboxylic acid (70.4 g, 0.41 mol) in ethanol (300 ml) was saturated with hydrogen chloride prepared from the combination of concentrated hydrochloric acid (430 ml) and concentrated sulphuric acid (430 ml) at 0°. After standing overnight at room temperature, the reaction mixture was evaporated to dryness yielding 77.1 g (94%) of an oil which crystallized after seeding, m.p. 81°-86°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].F[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>CCO>[CH3:11][C:4]1[S:3][C:2]([NH:1][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[N+:20]([O-:22])=[O:21])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: COC(=O)c1cc(C)sc1N
Solvent: CCO
Product: COC(=O)c1cc(C)sc1Nc1ccc(F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-amino-5-methyl-thiophene-3-carboxylate and 2,5-difluoronitrobenzene, m.p. 149°-151° C. (EtOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:45][CH2:44][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=4)[C:33]([O:35]C(C)(C)C)=[O:34])[C:18]3=[O:43])[CH2:16][CH2:15]2)[C:3]1=[O:46].Cl>O1CCOCC1.C([SiH](CC)CC)C>[CH3:1][C:2]1([CH3:47])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:45][CH2:44][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:29][C:30]4[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=4)[C:33]([OH:35])=[O:34])[C:18]3=[O:43])[CH2:16][CH2:15]2)[C:3]1=[O:46]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C(C)(C)c5ccccc54)CC3)C2=O)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2cccc(C(=O)O)c2)CN3c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 3-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.16 g, 0.25 mmol) was added 4M solution of HCl in dioxane (2.5 mL) and triethylsilane (0.05 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.14 g, 90%); 1H NMR (DMSO-d6): δ 1.28 (s, 6H), 1.91 (d, 2H, J=14 Hz), 2.07 (br, 2H), 2.71 (t, 2H, J=10 Hz), 3.17 (br, 2H), 3.45-3.71 (m, 4H), 3.76 (t, 2H, J=7.2 Hz), 4.62 (s, 4H), 7.04-7.07 (m, 5H), 7.15 (d, 1H, J=7.6 Hz), 7.27 (t, 1H, J=8 Hz), 7.36 (d, 1H, J=7.6 Hz), 7.50 (t, 1H, J=8 Hz), 7.55 (d, 1H, J=7.6 Hz), 7.87 (dd, 2H, J=6.8 and 1.6 Hz), 10.39 (br, 1H), 13.03 (br, 1H); MS for C34H37FN4O4 m/z 585.23 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH2:27][CH3:28])=[N:25][N:24]=[N:23]3)[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:27]([C:26]1[N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:30])([CH3:29])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[N:23]=[N:24][N:25]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3CC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 93.1 %

Procedure:
To a stirred mixture solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.5 g, 3.7 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.3 g, 90%) as a off-yellow solid: LC/MS m/e calcd for C21H23N5O2 (M+H)+: 378.45, observed: 378.2.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([CH:17]1[O:22][CH2:21][CH2:20][NH:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:10]([CH:17]1[O:22][CH2:21][CH2:20][N:19]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: c1ccc(CC2CNCCO2)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(CN2CCOC(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1.5 eq. of 4-Bromobenzyl bromide and 1 eq. of 2-Benzyl-morpholine in acetonitrile could be stirred at room temperature and 3 eq. of potassium carbonate could be added. The reaction could be stirred at room temperature overnight. The solution could be filtered through Celite and concentrated in vacuo to afford a brown solid. Purification could be done by flash chromatography to afford product.
Reaction SMILES: OC1C([N+]([O-])=O)=CC=CC=1C(O)=O.S(Cl)(Cl)=O.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([NH2:26])=[O:25])[C:22]=1[OH:30])([O-])=O.[S]>CN(C)C1C=CN=CC=1.[Ni].[Pd].C(N(CC)CC)C>[NH2:18][C:21]1[CH:29]=[CH:28][CH:27]=[C:23]([C:24]([NH2:26])=[O:25])[C:22]=1[OH:30]
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Ni]
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cccc(N)c1O

Procedure:
A preferred synthesis of the desired product acylated aminosalicylamides (Formula I) is shown in the following Scheme 1. 2-Hydroxy-3-nitrobenzoic acid 1 was converted to the acid chloride 2 with excess thionyl chloride. After removal of the excess thionyl chloride, the crude acid chloride 2 was reacted with the desired amine 3 in dichloromethane solution containing triethylamine as an acid scavenger and 4-dimethylaminopyridine (DMAP) as a catalyst. Crude 3-nitrosalicylamide 4 could be isolated after washing the reaction mixture with dilute HCl solution, drying, and evaporation of the solvent. Usually 4 was of sufficient purity to carry forward to the final product 6, but if desired could be purified by recrystallization or chromatography or a combination of both. In some cases where the 3-nitrosalicylamide 4 is a mixture of diastereomers, one might choose to isolate the individual diastereomers at this stage. However, since all of the various diastereomers are fungicidally active, this is not necessary. The 3-nitrosalicylamide 4 was subsequently reduced under catalytic hydrogenation conditions using Pd, Pt, or Ni catalysts either unpoisoned or poisoned with sulfur or lead. The 3-aminosalicylamide 5 usually was not isolated, but immediately reacted with excess acetic-formic anhydride. Isolation of the AASA product 6 was a simple matter of filtration, washing with sodium bicarbonate solution, drying and evaporation of the solvent. The crude product 6, usually a solid foam or glass, often was of sufficient purity to be directly submitted for testing. However, if desired, it could be further purified by recrystallization or chromatography or a combination of both.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[C:4]([O:6]CC)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/C(=O)O
Temperature: 50 °C

Procedure:
Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexaenoate (3) was dissolved in methanol (9 ml) and added LiOH (220 mg, 4.89 mmol) in water (3 ml) and the mixture was heated at 50° C. for 2 hrs. The mixture was cooled, and diluted hydrochloric acid was added to pH 2. Extraction with diethylether, drying (MgSO4) and evaporation of solvents under reduced pressure afforded the acid 4. The acid was purified by flash chromatography on silica gel (8:2 hexane-EtOAc); δH(300 MHz) 0.95 (t, J 7.5, 3H, CH3), 1.55 (m, 2H), 2.0-2.2 (m, 6H), 2.15 (d, J 1.3, 3H, CH3), 2.7-2.9 (m, 8H), 5.2-5.5 (m, 10H), 5.68 (br s, 1H); δc(75 MHz) 14.24, 19.04, 20.53, 25.51, 25.60, 25.62, 25.64, 26.67, 27.28, 40.67, 115.24, 126.99, 127.84, 128.05, 128.11, 128.19, 128.22, 128.53, 128.57, 129.23, 132.00, 163.05, 172.31.
Reaction SMILES: [N:1]1([CH:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][CH:15]=2)[C:8]#[N:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>CO.[Ni]>[N:1]1([CH:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][CH:11]=2)[CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#CC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.2 %

Procedure:
A mixture of morpholin-4-yl-(2-trifluoromethyl-pyrimidin-5-yl)-acetonitrile (200 mg, 0.735 mmol), Raney-Ni (200 mg), NH3 (aq) (1.5 mL) in MeOH (20 mL) was degassed and purged with Ar and H2 each 3 times. The mixture was stirred at room temperature under H2 (30 psi) for 25 minutes. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to yield the title compound (175 mg, yield: 86%). 1H NMR (CDCl3 400 MHz): δppm 8.83 (s, 2H), 3.80-3.61 (m, 4H), 3.44 (t, J=5.2 Hz, 1H), 3.19-2.99 (m, 2H), 2.52-2.35 (m, 4H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][C:6]1([CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][N:19]=3)[CH:14]=2)[O:9][CH2:8][CH2:7]1>CCOCC>[CH3:5][C:6]1([CH3:26])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([OH:25])[CH2:1][CH3:2])=[CH:20][N:19]=3)[CH:14]=2)[O:9][CH2:8][CH2:7]1
Reactant: CC[Mg]Br
Reactant: CC1(C)CCOc2ccc(C#Cc3ccc(C=O)cn3)cc21
Solvent: CCOCC
Product: CCC(O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Reaction time: 1 h

Procedure:
Four ml of a 3M (12 mmol) solution of ethylmagnesium bromide in ether is placed in a B-necked flask fitted with a mechanical stirrer, a reflux condenser protected by a drying tube and a pressure-equalizing dropping funnel protected by a drying tube. The flask is cooled in an ice bath and a solution of 2.8 g (10 mmol) of 2-(2-(4,4-Dimethylchroman-6-yl) ethynyl)-pryidine-5-carboxaldehyde in 10 ml of dry ether is added slowly with vigorous stirring. The cooling bath is then removed and the mixture heated at reflux for 3 hours. The mixture is then cooled in an ice-salt bath and 5 ml of saturated ammonium chloride solution added. The mixture is stirred for a further 1 hour and then filtered and the residue washed with two 10 ml portions of ether. The ether solution is then separated, dried (MgSO4) and the ether removed in vacuo. The residue is then purified by chromatography followed by recrystallization to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCCN2CCN(C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1cc(CCCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 31.8 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (110 mg, 0.22 mmol), 22-(methyloxy)-4-[3-(4-methyl-1-piperazinyl) propyl]aniline (Example 141, step B) (53 mg, 0.20 mol), and p-toluenesulfonic acid (102 mg, 0.54 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (50 mg, 0.07 mmol, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.36 (d, J=6.78 Hz, 1H), 8.49 (s, 1H), 8.25 (d, J=5.13 Hz, 1H), 8.10 (d, J=2.20 Hz, 1H), 7.76 (dd, J=8.61, 2.20 Hz, 1H), 7.67-7.73 (m, 1H), 7.63 (d, J=7.87 Hz, 1H), 7.40-7.45 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.13-7.21 (m, 2H), 6.94-6.98 (m, 1H), 6.93 (d, J=1.65 Hz, 1H), 6.74 (dd, J=8.06, 1.65 Hz, 1H), 6.58 (d, J=5.31 Hz, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 2.56 (t, J=7.60 Hz, 2H), 2.32-2.42 (m, 2H), 2.20-2.32 (m, 8H), 2.09-2.13 (m, 3H), 1.67-1.76 (m, 2H). MS (ESI): 719 [M+H]+.
Reaction SMILES: [Br:1][C:2]([Br:5])([Cl:4])[Cl:3].[Sb](Cl)(Cl)[Cl:7].ClCl>>[Cl:7][C:2]([Cl:3])([Cl:4])[Br:5].[Br:1][C:2]([Br:5])([Cl:4])[Cl:3]
Reactant: Cl[Sb](Cl)Cl
Agent: ClC(Cl)(Br)Br
Agent: ClCl
Product: ClC(Cl)(Cl)Br
Temperature: 110 °C

Procedure:
Dibromodichloromethane (4.3 moles, CBr2Cl2) and 0.5 mole of antimony trichloride (SbCl3) were placed in a one liter flask. The flask was equipped with a gas inlet for the introduction of chlorine and with a four bulb reflux condenser heated with atmospheric steam. The flask was heated to 110° C. and 2.2 moles of chlorine were then introduced into the mixture. The resulting reaction was exothermic. The reaction temperature was maintained within the range of 107° to 118° C. for about 1.5 hours. Bromine and low boiling organics were continuously distilled from the top of the condenser and condensed in an ice cooled trap. Fractionation of the recovered organic material yielded 8.4 mole percent carbon tetrachloride (CCl4), 63.3 mole percent of trichlorobromomethane (CBrCl3), and 22.6 mole percent dibromodichloromethane (CBr2Cl2). The total recovery was 94.4 mole percent. Eighty-four percent of the bromine was recovered, excluding that which remained in the residual antimony salts.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]34[O:26][CH:17]3[CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH2:23][CH2:24][C:25]=34)=[CH:15][C:10]=2[O:9][CH2:8]1>C1(C)C=CC=CC=1>[O:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:17]3=[O:26])=[CH:15][C:10]=2[O:9][CH2:8]1
Reactant: C1=CC2=C(CC1)C1(c3ccc4c(c3)OCO4)OC1CC2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C1CCc2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 80 °C

Procedure:
6.0 Grams (0.05 mols) of magnesium sulfate and 500 mL of toluene were added to 53.3 g (0.20 mols) of 7b-benzo[1,3]dioxole-5-yl-1a,2,3,7-tetrahydro-1-oxacyclopropa[a]naphthalene, and the mixture was heated at 80° C. for 2 hours. After cooled, the reaction product was washed two times each with 250 mL of water, and the organic layer was condensed under reduced pressure to obtain 1-benzo[1,3]dioxole-5-yl-3,4-dihydro-1H-naphthalene-2-one represented by the following formula,