Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]([NH:14][CH:15]([C:27]([O:29]C)=[O:28])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[NH:19][CH:18]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9].Cl.COC(=O)[C@H](CC1C2C(=CC=C(O)C=2)NC=1)N>O.[OH-].[Na+].CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]([NH:14][CH:15]([C:27]([OH:29])=[O:28])[CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([OH:26])[CH:24]=3)[NH:19][CH:18]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COC(=O)C(Cc1c[nH]c2ccc(O)cc12)NC(=O)C=Cc1ccc(O)c(OC)c1
Agent: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=CC(=O)NC(Cc2c[nH]c3ccc(O)cc23)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
3-(3-Methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-methoxycarbonylethyl]-2-propenamide synthesized from 5-hydroxy-L-tryptophan methyl ester hydrochloride (704 mg, 2.6 mmol) in the same manner as in Example 18 was dissolved in a mixed solvent of water (11.8 ml), 2.5N NaOH aqueous solution (11.8 ml), and N,N-dimethylformamide (23.6 ml) without purification, and the mixture was stirred at room temperature overnight. The reaction solvent was concentrated under reduced pressure, cooled to 0° C., and adjusted with 6N aqueous HCl solution to pH 1 to 2. The solution was extracted three times with ethyl acetate (30 ml), and the organic layer was washed with 3N HCl (20 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (PTLC, eluent: chloroform:methanol=3:1) to give 3-(3-methoxy-4-hydroxyphenyl)-N-[2-(5-hydroxy-1H-indol-3-yl)-1-hydroxycarbonylethyl]-2-propenamide (147 mg, yield 15.4%) as a powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:33])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([N:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[O:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1.Cl>C(O)(C)C.O1CCOCC1>[C:35]1([NH:1][C:2]2[C:3]([CH3:33])=[C:4]([C:8]3[C:20]4[C:19]5[C:14](=[CH:15][C:16]([C:21]([N:23]6[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]6)=[O:22])=[CH:17][CH:18]=5)[NH:13][C:12]=4[C:11]([C:30]([NH2:32])=[O:31])=[CH:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Cc1c(N)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Reactant: Clc1nccc2ccccc12
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(Nc2nccc3ccccc23)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)N4CCN(C)CC4)ccc3c12
Temperature: 140 °C
Yield: 35.6 %

Procedure:
A suspension of 4-(3-amino-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide (Example 3-2, 35 mg, 0.079 mmol) and 1-chloroisoquinoline (19.45 mg, 0.119 mmol) in isopropanol (0.5 mL) was treated with 4M hydrogen chloride in 1,4-dioxane (3 drops) and the mixture was heated in a sealed tube by microwave irradiation at 140° C. for 45 min. Additional 4 M hydrogen chloride in 1,4-dioxane (1 drop) was added and the mixture was again heated in a sealed tube by microwave irradiation at 140° C. for 60 min. The mixture was concentrated and the residue was purified by preparative HPLC. The appropriate effluent fractions were concentrated and the residue was partitioned between NaHCO3 (aq) and EtOAc, and the aqueous phase was extracted twice more with EtOAc. The combined organic phases were dried and concentrated to provide 4-(3-(isoquinolin-1-ylamino)-2-methylphenyl)-7-(4-methylpiperazine-1-carbonyl)-9H-carbazole-1-carboxamide as a white solid (16 mg, 32%). 1H NMR (400 MHz, methanol-d4) δ 8.28 (1H, d, J=8.3 Hz), 7.91 (1H, d, J=7.8 Hz), 7.72 (1H, d, J=6.1 Hz), 7.66 (1H, d, J=8.3 Hz), 7.56-7.61 (2H, m), 7.48 (1H, ddd, J=8.0, 7.2, 0.8 Hz), 7.44 (1H, d, J=7.5 Hz), 7.34 (1H, t, J=7.8 Hz), 7.22 (1H, d, J=8.0 Hz), 7.14 (1H, d, J=6.7 Hz), 7.06 (1H, d, J=7.8 Hz), 6.97 (1H, d, J=6.1 Hz), 6.94 (1H, dd, J=8.2, 1.5 Hz), 3.71 (2H, br. s.), 3.42 (2H, br. s.), 2.45 (2H, br. s.), 2.32 (2H, br. s.), 2.23 (3H, s), 1.81 (3H, s). Mass spectrum m/z 569.4 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]2[CH:16]=[C:17]3[C:22](=[C:23]([CH:25]([CH3:27])[CH3:26])[CH:24]=2)[O:21][C:20]([CH3:29])([CH3:28])[CH2:19][C:18]3([CH3:31])[CH3:30])[CH:8]=1)C.[OH-].[K+]>C(O)C.O1CCCC1>[CH:25]([C:23]1[CH:24]=[C:15]([C:14]#[C:13][C:9]2[CH:8]=[C:7]([CH:6]=[CH:5][C:4]([OH:32])=[O:3])[CH:12]=[CH:11][CH:10]=2)[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([CH3:28])([CH3:29])[CH2:19][C:18]2([CH3:31])[CH3:30])([CH3:27])[CH3:26]
Reactant: CCOC(=O)C=Cc1cccc(C#Cc2cc(C(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#Cc2cccc(C=CC(=O)O)c2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A solution of 3-[3-(8-isopropyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)-phenyl]-acrylic acid ethyl ester (Intermediate 33, 0.058 g, 0.13 mmol) in ethanol (2 mL) and tetrahydrofuran (2 mL) was treated with a 5N solution of potassium hydroxide (2 mL, 10 mmol) and the reaction mixture was stirred at ambient temperature overnight. The Volatiles were evaporated in vacuo, the residue was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated to afford the title compound (0.036 g, 66%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH3:18].[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[C@@H:12]([CH3:16])[CH2:11]2)=[CH:6][C:5]=1[O:17][CH3:18]
Reactant: COc1cc(N2CCN[C@@H](C)C2)ccc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)[C@@H](C)C2)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (S)-1-(4-Chloro-3-methoxyphenyl)-3-methylpiperazine dihydrochloride and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[(S)-4-(4-chloro-3-methoxyphenyl)-2-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.66 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.29-7.19 (m, 4H), 6.44-6.39 (m, 2H), 5.42 (br. s, 2H), 4.83 (br. s, 0.3H), 4.49 (br. s, 0.3H), 4.30 (br. s, 0.3H), 3.89 (s, 1.2H), 3.88 (s, 1.8H), 3.83 (br. s, 0.3H), 3.72-3.69 (m, 1H), 3.54-3.52 (m, 1H), 3.38 (br. s, 1H), 3.19-3.15 (m, 1H), 3.00 (br. s, 1H), 2.80 (br. s, 1H), 1.50-1.43 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2].[F-].[K+].[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Br)=[O:19]>C(#N)C.[OH-].[Na+]>[CH:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH2:23][C:22]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:18]([O:17][CH3:16])=[O:19])[C:6]2=[N:5][C:4]=1[CH3:13])=[O:2]
Reactant: Cc1nc2c(O)cccn2c1C=O
Reactant: COC(=O)Nc1cccc(C)c1CBr
Agent: [F-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)Nc1cccc(C)c1COc1cccn2c(C=O)c(C)nc12
Temperature: 25 °C
Yield: 64.9 %

Procedure:
2.6 g of 3-formyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine are dissolved in 50 ml of dry acetonitrile with exclusion of moisture at 50° C. and, after cooling to RT, 2.8 g of commercial potassium fluoride (50% by weight) on kieselguhr (for example Celite®) are added. A solution of 3.6 g of 2-methoxycarbonylamino-6-methylbenzyl bromide in 50 ml of dry acetonitrile is added dropwise, and the mixture is heated at 70° C. for 6 h. After cooling to RT, the mixture is poured into ice-water, adjusted to pH 9 with a few drops of 6N sodium hydroxide solution and extracted with ethyl acetate. The collected organic phases are washed with water and dried over sodium sulfate. Stripping off the solvent in vacuo and stirring in a little cold methanol result in 3.2 g of the title compound of m.p. 196°-198° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[C:27]([CH3:50])=[N:28][N:29](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:30]=5)[CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:51]>>[ClH:51].[ClH:51].[C:1]1([NH:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[C:27]([CH3:50])=[N:28][NH:29][CH:30]=5)[CH:24]=4)[N:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)Nc4ccccc4)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(=O)Nc4ccccc4)CC3)c2c1

Procedure:
63 mg N1-phenyl-4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 181 and 0.7 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 30 mg of the title compound as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[NH2:15][CH:16]1[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C:17]1([CH3:32])[CH3:31].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:15][CH:16]3[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][C:17]3([CH3:32])[CH3:31])=[C:8]([C:11](=[O:12])[NH2:13])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC1(C)CN(C(=O)OCc2ccccc2)CC1N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)OCc2ccccc2)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 63.0 mg, 0.230 mmol) in N,N-dimethylformamide (0.5 mL), was added benzyl 4-amino-3,3-dimethylpyrrolidine-1-carboxylate (Intermediate 11, 57 mg, 0.230 mmol) and N,N-diiospropylethylamine (0.121 mL), and heated at 90° C. for 16 h. The reaction was added water, stirred at rt for a 3 hours and filtered. The solid was rinsed with water and dried under vacuum to give benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpyrrolidine-1-carboxylate (72 mg, 64.5% yield) as a yellow solid. 1H NMR (400 MHz, METHANOL-d4) δ 10.83-10.77 (m, 1H), 8.16 (s, 1H), 7.67 (s, 1H), 7.41-7.27 (m, 7H), 7.09-7.04 (m, 1H), 5.18-5.08 (m, 2H), 4.56-4.45 (m, 1H), 4.16-3.95 (m, 1H), 3.42 (d, J=2.2 Hz, 3H), 1.20 (d, J=13.9 Hz, 6H); MS (ES+) m/z: 486.4, 487.9 (M+H); LC retention time: 4.02 min (analytical HPLC Method I).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH3:9])C(=O)C2=CC=CC=C12.[ClH:29]>>[ClH:29].[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:8]([CH3:9])[CH2:7][CH2:6][NH2:5])=[CH:11][CH:12]=2)=[CH:21][CH:20]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
37.3 g of 1-phthalimido-3-(4'-fluoro-4-biphenylyl)- butane are boiled for 6 hours with 400 ml of 20% aqueous hydrochloric acid, evaporated and worked up using sodium hydroxide solution and ether to give 3-(4'-fluoro-4-biphenylyl)-butylamine, hydrochloride, m.p. 222°- 224°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:23])[CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17]OS(C)(=O)=O)[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:24]#[N:25].[Na+]>CN(C)C=O.CCOCC>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][C:24]#[N:25])[CH2:13][CH2:12]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC[C@H]1CC[C@H](COS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C

Procedure:
A solution of 12.64 g (36.17 mmol) of trans-methanesulfonic acid 4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexylmethyl ester (example 13.1) and 4.51 g (92 mmol) of sodium cyanide in 100 ml of dimethylformamide was stirred for 6 hours at 110° C. The reaction mixture was then taken up in ether and washed four times with water. The ether layer was dried over sodium sulfate and concentrated under reduced pressure, giving 10.14 g of crude trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester as a colorless oil, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 250 mL 3 neck flask with mechanical stirring and condenser, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle and under nitrogen atmosphere, the following was added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethyl-piperidine hydrochloride, 16.59 g of powdered potassium carbonate and 60 mL of ethyl acetate. The mixture was heated slowly to reflux. After overnight reflux, the mixture was cooled to ambient temperature, after which 60 mL of deionized water was added. The aqueous layer was separated and discarded. The organic layer was extracted with 4N hydrochloride (3 aliquots of 20 mL). The combined acid extracts were heated to reflux. After 1 hour at reflux, HPLC indicated the saponification to be 609 complete. After 4 hours, the reaction was near 100% complete. The mixture was cooled to 0° C.-5° C. and stirred. The resulting crystals were filtered, rinsed with acetone and dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.Cl.[N:11]1([CH2:16][CH2:17][C:18](O)=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:18](=[O:19])[CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[NH2:9])=[N:6][CH:7]=1
Reactant: O=C(O)CCN1CCCC1
Reactant: NNc1ccc(F)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NN(C(=O)CCN1CCCC1)c1ccc(F)cn1
Reaction time: 18 h

Procedure:
5-fluoro-2-hydrazinopyridine (285 mg, 2.24 mmol) and 3-(pyrrolidin-1-yl)propanoic acid hydrochloride (400 mg, 2.24 mmol) were dissolved in DMF (15 mL). EDC (516 mg, 2.69 mmol), HOBt (30.0 mg, 0.22 mmol) and triethylamine (374 μL, 2.69 mmol) were added and the reaction stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, which was washed with MeOH then with 2M NH3 in MeOH. The basic fractions were evaporated in vacuo then purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound contaminated with several impurities (400 mg). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH3:15][N:16](C=O)C>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:13][CH2:12][CH2:11][CH:10]1[C:5]2[CH:4]=[CH:3][C:2]([C:15]#[N:16])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1
Reactant: CN(C)C=O
Reactant: OCCC1OCCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)CCOC2CCO

Procedure:
2-(6-Bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (1.3 g, 5.1 mmol), zinc cyanide (0.36 g, 3 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.23 g, 0.20 mmol) were stirred in degassed DMF (20 mL) under nitrogen at reflux for 9 h. The reaction mixture was diluted with toluene and washed with 2M aqueous ammonia, the aqueous layer further extracted with ethyl acetate, then the combined organic extracts washed with brine. The organic extracts were dried (MgSO4), filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (30:70 to 0:100), yielded the title compound as a light brown oil.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH:15]=[O:16].O.C(OCC)(=O)C>CS(C)=O>[CH2:9]([N:8]1[C:4]([F:1])=[C:5]([CH:15]=[O:16])[C:6]([C:11]([F:14])([F:13])[F:12])=[N:7]1)[CH3:10]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1nc(C(F)(F)F)c(C=O)c1F
Temperature: 100 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
34.3 g (591.3 mmoles) of potassium fluoride (a spray-dried product) was added, at room temperature, into a solution of a crude product of 5-chloro-1-ethyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde (equivalent to 197.1 mmoles) dissolved in 100 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 3 days to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 11.1 g (yield: 26.8%) of 1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.ClC(OCC(C)C)=O.Cl.[CH3:27][NH:28][O:29][CH3:30]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([C:8]([N:28]([O:29][CH3:30])[CH3:27])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ncccc1Br
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)c1ncccc1Br
Temperature: 25 °C

Procedure:
To a solution of 3-bromopyridine-2-carboxylic acid (3-1; 250 mg, 1.24 mmole) in CH2Cl2 (5 mL) was added Et3N (0.21 mL, 3.72 mmole) then isobutyl chloroformate (0.19 mL, 1.49 mmole) at 0° C. After 30 minutes N,O-dimethylhydroxylamine hydrochloride (181 mg, 1.86 mmole) was added. After 15 minutes the mixture was warmed to RT. After 18 hr the mixture was diluted with H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (50% EtOAc/hexanes) gave the title compound (3-2) as a clear oil: 1H-NMR (500 MHz, CDCl3) δ 8.56 (m, 1H), 7.92 (m, 1H), 7.24 (m, 1H), 3.58 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.Cl[CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)(C)C(=O)CCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC(=O)C(C)(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with 1-chloro-3,3-dimethyl-2-butanone according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)4-isobutyl-3-(2-oxo-3,3-dimethyl-1-butyl)-1,3-thiazolidine.
Reaction SMILES: [P:1]([O:16][C:17]1[CH:22]=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:27][CH2:28][CH2:29][O:30]C(O)C)[CH2:24][CH2:25][CH3:26].[OH-].[Na+]>>[P:1]([O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:16][CH2:17][CH2:22][O:30][CH2:29][CH2:28][O:27][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCOCCOC(C)O
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOCCOCCOP(Oc1ccccc1)Oc1ccccc1

Procedure:
248.2 g. (0.8 mol) of triphenyl phosphite and 131.2 g (0.81 mol) of 2-butoxyethoxyethanol were put into a flask of 500 ml. and 0.1 g. of sodium hydroxide was added thereto to react at 140°C. for 4 hours. The liberated phenol was distilled away by distillation under a reduced pressure (at 60°C. under 5 mm.Hg). Then the residual solution was filtered to obtain colorless transparent 2-(2-butoxyethoxy)ethyl diphenyl phosphite (Compound 9) as a filtrate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:16]1([CH:12]2[O:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)N1CCOC(c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCOC(c2ccccc2)C1
Temperature: 120 °C
Yield: 97 %

Procedure:
100 mg of (4-Bromo-phenyl)-(2-phenyl-morpholin-4-yl)-methanone was combined with 82 mg of 2-(Trifluoromethyl)phenyl boronic acid, 33 mg of tetrakis(triphenylphosphine)palladium(0), 0.968 mL of 2M sodium carbonate solution, 2.6 mL toluene and 1.3 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by reverse phase HPLC. ES MS (+) m/z 412, 97% yield.