Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:22](=[O:25])[CH2:23][CH3:24])[C:10]2[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=2[CH:21]=1)(=O)=O.[CH3:28]O.[CH3:30][C:31]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:36][CH2:35][N:34]([C:37]2[N:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][N:38]=2)[CH2:33][CH2:32]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH2:30]([C:31]1([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:32][CH2:33][N:34]([C:37]2[N:38]=[CH:39][C:40]([C:7]3[CH:8]=[C:9]([C:22](=[O:25])[CH2:23][CH3:24])[C:10]4[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=4[CH:21]=3)=[CH:41][N:42]=2)[CH2:35][CH2:36]1)[CH3:28]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)CC)c2s1
Reactant: CO
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C(=O)CC)c2s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 2-(3-ethylureido)-7-propionylbenzo[d]thiazol-5-yl trifluoromethanesulfonate (Intermediate 13) (0.25 g, 0.587 mmol) in 1,4-dioxane:MeOH (21 mL: 14 mL) were added ethyl 4-methyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.46 g, 1.17 mmol) and potassium phosphate (0.19 g, 0.88 mmol) at rt under N2 atmosphere. The reaction mixture was degassed by N2 for 15 min followed by addition of tetrakis (triphenylphosphine)palladium(0) (0.068 g, 0.058 mmol). The reaction mixture was further degassed by N2 for 15 min then stirred for 2 h at 80° C. After the completion of reaction (by TLC), water (50 mL) was added, extracted with EtOAc (3×50 mL) and the combined organic layers washed with water, brine, dried over anhydrous Na2SO4, filtered then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100-200 M, 70% EtOAc-hexane) to afford the desired product as an off-white solid (0.110 g, 35%). 1H NMR (DMSO-d6): δ 10.70 (br s, 1H), 8.87 (s, 2H), 8.23 (s, 1H), 8.14 (s, 1H), 6.80 (br s, 1H), 4.47 (m, 2H), 4.17 (q, J=7.20 Hz, 2H), 3.33 (m, 2H), 3.12-3.22 (m, 4H), 2.09 (m, 2H), 1.56 (q, J=7.60 Hz, 2H), 1.39 (m, 2H), 1.22 (t, J=7.20 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H) and 0.75 (t, J=7.2 Hz, 3H). MS: 539.52 [M+H]+
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC(C)C)(C)C.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Solvent: CC(C)OC(C)C
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 83 °C
Yield: 94.9 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Diisopropyl ether (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 20 hours while agitating at an internal temperature of 83° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure, and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of isopropyl ether that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.9 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 94% based on benzenesulfonyl cyanide).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[C:21]([NH2:26])=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[C:21]2[NH2:26])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(N)nccc2cc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-amino-7-methylisoquinolin4-ol (430 mg, 2.4 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g) and K2CO3 (510 mg, 3.7 mmol) in anhydrous N, N-dimethylformamide (8 ml) were microwaved at 100° C. for 10 minutes. A further equivalent of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester in N, N-dimethylformamide (4 ml) was added and the mixture microwaved at 100° C. for a further 10 minutes. The mixture was diluted with water, acidified with acetic acid and further diluted with methanol. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using flash chromatography on silica (eluent: 9:1:0.1 dichloromethane : methanol :ammonium hydroxide) to afford 4-(1-amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (327 mg). A mixture of the 4-(1-amino-7-methylisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol to give 7-methyl-6-(piperidin-4-yloxy)isoquinolin-1-ylamine (270 mg), El-MS: m/z=258.4 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]5[CH2:34][CH2:35][CH2:36][CH2:37]5)=[CH:26][CH:25]=4)[N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenyl)-carbamic acid tert-butyl ester (1.39 g, 2.71 mmol) was dissolved in dichloromethane (10 ml). Trifluoroacetic acid (10 ml) was added and the reaction mixture stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice with dichloromethane, and the combined organics washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield 830 mg, 74%. 50 mg was purified by preparatory LCMS.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](COCC[Si](C)(C)C)[N:10]=[C:9]2[O:23][CH3:24].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[O:23][CH3:24]
Reactant: COc1nn(COCC[Si](C)(C)C)c2ccc(C3OCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COc1n[nH]c2ccc(C3OCCO3)cc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To 940 mg (2.682 mmol) 5-(1,3-dioxolan-2-yl)-3-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 21A) and 805 mg (13.41 mmol) ethane-1,2-diamine in THF (50 ml) were added 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF). The reaction mixture was heated to 50° C. for 3 h. After this time, 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF) were added again, and heating was continued for further 12 h until conversion was complete. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated, and the remaining solid was purified by chromatography on silica gel (cyclohexane/ethyl acetate gradient) to afford 556 mg (94% of th.) of the intermediate compound 5-(1,3-dioxolan-2-yl)-3-methoxy-1H-indazole [LC-MS (method 2): Rt=1.44 min; MS (ESIpos): m/z=211 (M+H)+]. This material was dissolved in ethanol (37 ml), treated with 1 N hydrochloric acid (9.4 ml) and heated to 90° C. for 30 minutes. After this time, the mixture was evaporated to dryness, and the crude aldehyde thus obtained was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:10]=1[CH2:11][NH:12][C:13]1[N:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1>[NH2:16][CH2:15][C:14]1[C:13]([NH:12][CH2:11][C:10]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:9]=2[O:8][CH3:7])=[N:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncccc2CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was added slowly to a solution of 2-[(2,4-dimethoxybenzyl)amino]nicotinonitrile (2.80 g, 10.4 mmol) in tetrahydrofuran (35 mL) at 0° C. The reaction was allowed to warm to room temperature and stir for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.92 g). MS 274,3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=2)[N:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH:18]S(O)(=O)=O>>[C:8]([C:7]1[CH:6]=[N:5][N:4]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[C:3]2[C:2]=1[Cl:1])(=[O:18])[NH2:9]
Reactant: CCOC(=O)c1cc2c(Cl)c(C#N)cnn2c1
Reactant: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(Cl)c(C(N)=O)cnn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a round bottom flask was added concentrated H2SO4 (100 mL) followed by ethyl 4-chloro-3-cyanopyrrolo[1,2-b]pyridazine-6-carboxylate (10 g, 40 mmol). The reaction was stirred at room temperature under nitrogen overnight. The reaction mixture was poured onto ice cold saturated sodium carbonate solution. The aqueous solution was extracted with EtOAc (4×) and the combined organic layer was concentrated to yield 7 g (70%) of the title compound as a yellow solid. HPLC (condition S): retention time=8.04 min. LCMS (condition A): m/z=268.0 +ve. 1H NMR (400 MHz, CDCl3) δ ppm: 8.49 (1H, d, J=1.6 Hz), 8.40 (1H, s), 8.08 & 7.98 (1H, two br s), 7.12 (1H, d, J=1.6 Hz), 4.34 (2H, q, J=7.2 Hz), 1.34 (3H, t, J=7.2 Hz).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:27]1[CH:26]=[CH:25][S:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[CH:35][CH:36]=3)[C:4](=[O:29])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 352, 200 mg, 0.4945 mmol) and THF (5.0 mL). To the resulting solution was added 4-(4-Amino-phenyl)-butyric acid (88.6 mg, 0.494 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (CHCl3:MeOH mix eluant with gradient of 1% MeOH to 15% MeOH) to afford the title compound in 43% yield (0.120 g, 0.212 mmol).
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:8]=[CH:7][C:6]1=2>C1(C)C=CC=CC=1>[OH:4][C:5]1([CH3:1])[CH2:14][CH2:13][CH2:12][C:11]2[N:10]=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: O=C1CCCc2nc(OCc3ccccc3)ccc21
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Product: CC1(O)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 92 %

Procedure:
Methylmagnesium bromide (3.0M in diethyl ether, 47 ml) was added dropwise to a solution of 5,6,7,8-tetrahydro-5-oxo-2-(phenylmethoxy)quinoline (29.6 g) and toluene (1l) at 0° C. The reaction mixture was allowed to warm to room temperature, with stirring. The reaction mixture was then quenched with saturated ammonium chloride solution, the layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to provide 31.7 g (92.0%) of product.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[NH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1.[BH4-].[Na+]>CO>[CH2:1]([NH:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH3:3]
Reactant: CCC=O
Reactant: NCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
Propanal (1.51 g) dissolved in 5 ml of methanol was added dropwise to 6.15 g of 2-aminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane dissolved in 60 ml of methanol. The mixture was stirred at room temperature for 30 minutes. Then, under ice cooling, 1.03 g of sodium borohydride was added to the mixture. The resulting mixture was stirred at the same temperature for 20 minutes and then stirred at room temperature for 1 hour. After methanol was removed, water was added to the residue, and the residue was extracted with ethyl acetate. The organic layer was collected by filtration, washed with water and dried, and the solvent was removed. The residue was purified by silica gel column chromatography (solvent; chloroform: methanol (15:1)) to obtain 5.22 g of 2-propylaminomethyl-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([NH:19][C:20](=[O:25])[C:21]([Cl:24])([Cl:23])[Cl:22])=[CH:14][C:13]=1[Cl:26]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:25])[C:21]([Cl:24])([Cl:22])[Cl:23])[CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][CH:1]=[O:3]
Reactant: Nc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1c(Cl)cc(NC(=O)C(Cl)(Cl)Cl)cc1Cl
Temperature: 5 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
Acetic anhydride (600 mL, 6.4 mol) and 90% formic acid (275 mL, 5.4 mol) are heated to reflux for 45 minutes and then cooled to 5° C. The N-(4-amino-3,5-dichlorophenyl)-trichloroacetamide (464 g., 1.44 mol) is added to the mixed anhydride solution and mechanically stirred for 20 hours at room temperature. Then the reaction mixture is poured onto ice (2 liters). When the stirred slurry reaches room temperature, it is collected by suction filtration and washed with water (1.5 liters) and dried to constant weight yielding 348.7 grams of N-(3,5-dichloro-4-formamidophenyl)-trichloroacetamide with a mass spectral analysis of m/e+· 348 for C9H5Cl5N2O2.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28].C(OC)(C)(C)C>C(Cl)Cl>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: Cc1cccnc1COc1ccn(CCc2ccc(CO)cc2)c(=O)c1
Reactant: BrP(Br)Br
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1cccnc1COc1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 280 mg (0.80 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(3-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 14.1a) in 8.0 mL of DCM is added 75 μL (0.80 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT and tert-butylmethylether is added. The formed precipitate is collected, washed with tert-butylmethylether and dried.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O>[F:1][C:2]([F:12])([F:13])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:21][CH2:22][OH:23]
Reactant: Oc1ccccc1OCC(F)(F)F
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccccc1OCC(F)(F)F
Temperature: 102.5 °C
Reaction time: 10 h
Yield: 56.5 %

Procedure:
To a mixture of 2-(2,2,2-trifluoroethoxy)phenol (XI) (6 g, 0.03 mole), N,N-dimethylformamide (50 ml) and potassium carbonate (13.0 g, 0.09 mole) was added 2-chloroethanol (4.2 ml, 0.06 mole). Reaction mixture was heated to 100-105° C. and stirred for 10 hours. Reaction mass was filtered and the filtrate was concentrated under reduced pressure to distill out the N,N-Dimethyl formamide. To the residue was added water and product was extracted in ethyl acetate (50 ml). The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 4.0 g of (XIV) as oil. Purity (By GC)=95%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][C:21]=3[O:35][CH3:36])[N:10]=2)=[C:4]([C:37](=[O:40])[NH:38][CH3:39])[CH:3]=1.ClC1N=C(NC2C=CC=CC=2C(NC)=O)C(C(F)(F)[F:60])=CN=1.NC1C(OC)=CC(CP(=O)(OCC)OCC)=CC=1F>>[F:60][C:34]1[CH:33]=[C:23]([CH:22]=[C:21]([O:35][CH3:36])[C:20]=1[NH:19][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=2[C:37](=[O:40])[NH:38][CH3:39])[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=1)[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(F)cc3C(=O)NC)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Agent: CCOP(=O)(Cc1cc(F)c(N)c(OC)c1)OCC
Product: CCOP(=O)(Cc1cc(F)c(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure from Example 102 (Diethyl (4-{[4-{[4-fluoro-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate) with 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-3-fluoro-5-methoxybenzyl)phosphonate (Compound 146A). 1H NMR (CD3OD, 400 MHz): δ=1.30 (t, J=7.07 Hz, 6H), 2.90 (s, 3H), 3.33-3.40 (m, 2H), 3.85 (s, 3H), 4.06-4.18 (m, 4H), 6.88 (dt, J=10.11, 2.02 Hz, 1H), 6.95 (s, 1H), 7.17 (br. s., 1H), 7.37 (br. s., 1H), 7.64 (d, J=6.82 Hz, 1H), 8.29 (br. s., 2H). MS (ES+): m/z 586.21 [MH+] (TOF, polar).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>C1(C)C=CC=CC=1.C(O)(C)C.O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH:17]([CH3:22])[CH3:18])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(I)ccc1O
Reaction time: 24 h

Procedure:
2-Hydroxy-5-iodobenzoic acid (184 g, 0.7 mol), isopropanol (50 ml), conc sulfuric acid (5 ml) and p-toluenesulfonic acid (10 g) in toluene (1l) was refluxed using a water separator. Portions of isopropanol was added intermittently to compensate for loss of 2-propanel by dehydration. After 24 h, the solution was cooled and washed with water. The toluene was evaporated partially. Iso-octane was added, and precipitated 2-hydroxy-5-iodobenzoic acid (106 g) filtered off. The solution was taken to dryness and the residue recrystallized from methanol. Yield 64 g, (71%, meted for recovered starting material).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][CH2:13]C(OCC)=O.[OH-:19].[Na+].[CH2:21]([OH:23])C>>[S:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[N:10][CH:11]([CH2:12][CH3:13])[C:21]([OH:23])=[O:19]
Reactant: [OH-]
Reactant: CCO
Reactant: CCOC(=O)CCCN=c1sc2ccccc2s1
Agent: [Na+]
Product: CCC(N=c1sc2ccccc2s1)C(=O)O

Procedure:
A solution of 4-[(1,3-benzodithiol-2-ylidene)amino]-butanoic acid, ethyl ester (3g, prepared as described in Example 5) and sodium hydroxide (427 mg) in 80% aqueous ethanol (50 ml) is stirred at room temperature for seven days. The reaction mixture is concentrated in vacuo and the residue triturated with two 50 ml portions of hot benzene. The solid residue is dissolved in 100 ml of water, filtered through Celite, and the filtrate treated with 10% hydrochloric acid until the pH is 4. The solid precipitate is collected by filtration and washed on the filter with water. Recrystallization of the solid product from chloroform yields 1.3g of the title compound, melting point 140°-142° C.