Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[C:8]([CH2:11][N:12]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:17][CH2:16][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:13]1)([OH:10])=[O:9].[OH-].[K+]>O1CCOCC1.O>[OH:5][CH:3]([C:2]([F:7])([F:6])[F:1])[CH2:4][N:21]1[CH2:22][CH2:23][N:12]([CH2:11][C:8]([OH:10])=[O:9])[CH2:13][CH2:14][N:15]([CH2:28][C:29]([OH:31])=[O:30])[CH2:16][CH2:17][N:18]([CH2:24][C:25]([OH:27])=[O:26])[CH2:19][CH2:20]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: FC(F)(F)C1CO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)C(F)(F)F)CCN(CC(=O)O)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
12.94 g (115.44 mmol) of (1,1,1-trifluoro-2,3-epoxypropane) and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 70° C. with exclusion of pressure. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent=gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.81 g (68% of theory) of a strongly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:26]1(C)C=CC=CC=1>CO>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:10][C:6]=1[C:7]([O:9][CH3:26])=[O:8]
Reactant: Cc1ccccc1
Reactant: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Yield: 98 %

Procedure:
A solution of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid (20 g) and thionyl chloride (15.0 g) in methanol (100 ml) was stirred at 80° C. for 2 hours. The solvents were evaporated under vacuum to give an oil residue. Toluene (100 ml) was added to the residue and the solution was washed with saturated NaHCO3 (30 ml) solution followed by water (3×30 ml). The organic layer was concentrated under reduced pressure to give the product as a white solid (20.5 g, yield 98.0%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)[Cl:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2)cs1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 83 %

Procedure:
To a suspension of N-(4-{2-[4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.383 g, 5.005 mmol) in anhydrous dichloromethane (60 ml) were added carbon tetrachloride (5.8 ml, 60 mmol) and triphenylphosphine (1.574 g, 6.000 mmol), and the mixture was stirred at room temperature for 22.5 hr. Triphenylphosphine (786.0 mg, 2.997 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 100 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(chloromethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (1.224 g, 4.153 mmol, yield 83.0%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][C:11]3[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=3[CH2:13][N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:14]([CH2:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:15]([CH3:18])(=[O:17])=[O:16]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(Nc5ccccc5CN(C)S(C)(=O)=O)cccn4n3)cc2)CC1

Procedure:
171 c) N-[2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-amino-benzyl)-N-methyl-methanesulfonamide (507.0 mg, 2.366 mmol) in a manner analogous to Example 2d. Product isolated as a tan foam (0.53 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.01 (d, J=6.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.10 (s, 1H), 6.90-6.81 (m, 2H), 4.36 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H). MS=366 (MH)+. 171 d) N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (d, J=6.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.00-6.94 (m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.36 (s, 2H), 3.18-3.13 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][C:13]1[CH:17]=[CH:16][N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1.CO[B:26]1[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]1>C1COCC1>[CH3:12][C:13]1[CH:17]=[C:16]([B:26]2[O:30][C:29]([CH3:32])([CH3:31])[C:28]([CH3:34])([CH3:33])[O:27]2)[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:14]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccn(C2CCCCO2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-methylpyrazole (3.0 g, 35.4 mmol), 3,4-dihydro-2H-pyrane (4.97 mL, 53.2 mmol) and TFA (0.02 mL, 0.260 mmol) was stirred at 85° C. for 6 h under an argon atmosphere. The RM was cooled to RT and NaH 60% in mineral oil (0.061 g, 1.524 mmol) was and the RM was stirred for 10 min. The RM was purified by bulb-to-bulb distillation to give 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (b.p. 150-170° C./12 mbar). A solution of n-BuLi in n-hexane (3.38 mL of 1.6 M, 5.41 mmol) was added dropwise over 10 min to a solution of 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.0 g, 5.41 mmol) in THF (12 mL) at −70° C. under a nitrogen atmosphere and The RM was stirred for 10 min and then treated dropwise with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.898 g, 5.69 mmol) and stirred at −70° C. for 1 h. The RM was allowed to warm to RT, treated with n-hexane and the product was filtered, dissolved in water (10 mL) and acidified to pH 6 with aqueous citric acid (10%). The water was evaporated off under reduced pressure and the aqueous residue extracted with EtOAc, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the title product as a yellow resin. UPLC-MS (Condition 3) tR=0.56 min, m/z=211.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.N1C=CC=CC=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C1C=CN=CC=1.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
In a 75 mL sealed tube, 4-bromopyrazole (1.0 g, 6.8 mmol), pyridine (21.0 mL, 258 mmol), triphenylmethyl chloride (2.1 g, 7.5 mmol), and 4-dimethylaminopyridine (0.17 g, 1.4 mmol) were added. The mixture was stirred at 80° C. for 24 hours. The mixture was diluted with water, and the solids which crashed out were filtered, rinsed with water and air-dried to yield 4-bromo-1-trityl-1H-pyrazole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=O)[C:11]2[C:12]([CH3:15])=[CH:13][S:14][C:10]=2[CH2:9]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[C:11]2[C:12]([CH3:15])=[CH:13][S:14][C:10]=2[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1csc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1csc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 171.3 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzothiophene-4-one (0.07 g), aminoguanidine hydrochloride (0.034 g), concentrated hydrochloric acid (0.063 ml), water (0.063 ml) and ethanol (10 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydrobenzothiophene hydrochloride (Compound 117) (80 mg) as colorless crystals.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@@H:11]1[C:20]([O:22]CC)=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].O>C1COCC1>[C:1]([NH:9][C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@@H:11]1[C:20]([OH:22])=[O:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC2(CC[C@H]1NC(=O)c1ccccc1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCC2(C[C@@H]1C(=O)O)OCCO2)c1ccccc1
Yield: 100 %

Procedure:
(7S,8R)-Ethyl 8-benzamido-1,4-dioxaspiro[4.5]decane-7-carboxylate (740 mg, 2.22 mmol) was dissolved in THF (10 mL) at 25° C. with stirring. 0.5N LiOH (8.88 mL, 4.44 mmol) was then added thereto and the mixture stirred for 3 hours. The reaction was worked up by adding water and then removing the THF in vacuo. The remaining basic aqueous mixture was then acidified to pH=3 with 1N HCl. The aqueous mixture was extracted (2×) with methylene chloride. The methylene chloride extracts were combined, dried over sodium sulfate and concentrated to give (7S,8R)-8-benzamido-1,4-dioxaspiro[4.5]decane-7-carboxylic acid (678 mg, 2.22 mmol, 100% yield) as a white glass. MS (ESI+)=306.19 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:45]=[CH:44][C:9]([CH2:10][C@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)[C@H:12]([OH:31])[CH2:13][N:14]([S:19]([C:22]2[CH:30]=[CH:29][C:25]3[O:26][CH2:27][O:28][C:24]=3[CH:23]=2)(=[O:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl[C:47]1[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([S:19]([N:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][C@@H:12]([OH:31])[C@@H:11]([NH:32][C:33](=[O:43])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:10][C:9]3[CH:44]=[CH:45][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:47]4[CH:52]=[CH:51][C:50]([C:53]#[N:54])=[CH:49][N:48]=4)=[CH:7][CH:8]=3)(=[O:21])=[O:20])=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCNc2ccc(C#N)cn2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution of 35 mg (0.054 mmol) of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-[4-(3-aminopropoxy)benzyl]3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxypropylcarbamate, 22 mg (0.16 mmol) of 2-chloro-5-cyanopyridine, and 38 μL (0.22 mmol) of N,N-diisopropylethylamine in 0.5 mL of anhydrous DMF was heated to 80° C. with stirring. After 6 hours the solution was cooled to RT and concentrated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford 33 mg (80%) of the desired compound as a white foam. 1H NMR (CDCl3): 8.30 (s, 1H), 7.50 (d, 1H), 7.29 (d, 1H), 7.13 (s, 1H), 7.09 (d, 2H), 6.84 (d, 1H), 6.78 (d, 2H), 6.37 (d, 1H), 6.04 (s, 2H), 5.62 (d, 1H), 5.44 (br s, 1H), 4.96 (m, 2H), 4.00 (t, 2H), 3.91 (m, 1H), 3.80 (m, 3H), 3.71-3.49 (m, 5H), 3.18-2.65 (m, 7H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.50 (m, 1H), 0.90 (d, 3H), 0.81 (d, 3H). MS(ESI): 752(M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[C:15]([NH2:19])[NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O[CH:23](OCC)[N:24]([CH3:26])[CH3:25])C>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:16]([C:17]#[N:18])=[C:15]([N:19]=[CH:23][N:24]([CH3:26])[CH3:25])[NH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Nc2n[nH]c(N)c2C#N)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(Nc2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 25 °C

Procedure:
A suspension of 5.3 g (20.7 mmol) of 3-(4-acetylamino-phenylamino)-5-amino-4-cyano-pyrazole in 4.4 ml (24.9 mmol) of N,N-dimethylformamide diethyl acetal (97%) and 100 ml of toluene is heated under reflux for 4 hours. The reaction mixture is then cooled to room temperature and filtered and the filter residue is washed with toluene, yielding the title compound having a water content of 4.22%; m.p. 275-276° C. (decomp.).
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([O-:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].[NH2+]1CCOCC1.Cl>O.CO>[OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(C=CC(=O)Nc2ccccc2C(=O)[O-])ccc1O
Agent: C1COCC[NH2+]1
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(C=CC(=O)Nc2ccccc2C(=O)O)ccc1O
Yield: 82.5 %

Procedure:
A 10 g quantity of morpholinium N-(4-hydroxy-3-methoxycinnamoyl)anthranilate is dissolved in a mixture of 80 ml of water and 60 ml of methyl alcohol with heating, and the resultant solution is added dropwise to 85 ml of diluted hydrochloric acid (5 ml of conc. hydrochloric acid and 80 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at 90°-100° C. under reduced pressure for 3 hours to yield N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (82.5% yield). The compound is confirmed as identical to that obtained in Example II.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([S:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=3[F:42])[N:27]=2)[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:43][C@H:44]([CH2:47][CH3:48])[CH2:45][OH:46]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([N:17]([C:26]2[CH:31]=[C:30]([NH:43][C@@H:44]([CH2:45][OH:46])[CH2:47][CH3:48])[N:29]=[C:28]([S:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=3[F:42])[N:27]=2)[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:23])[CH3:24])(=[O:15])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)N(COCC[Si](C)(C)C)c2cc(Cl)nc(SCc3cccc(Cl)c3F)n2)CC1
Product: CC[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc(SCc2cccc(Cl)c2F)n1
Temperature: 80 °C

Procedure:
The subtitle product of step i) (0.60 g) was diluted in (2R)-2-aminobutan-1-ol (2 ml) and heated at 80° C. for 18 h. The subtitle compound was recovered as a colourless oil by flash column chromatography (EtOAc/iso-hexane mixtures). Yield: 0.40 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9](B(O)O)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2].Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([O:3][C:4]1[C:9]([C:14]2[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1ncccc1B(O)O
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: COCCOC
Product: CCOc1ncccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
2-ethoxypyridine-3-boronic acid (0.123 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-10% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed from fractions containing product, resulting in 0.079 g in 80% yield.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:18][C:19](=[O:21])[CH3:20])[C:13]=1[O:14][C:15](=[O:17])[CH3:16])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[C:23]([O:28][CH2:29][CH2:30][NH2:31])(=[O:27])[C:24]([CH3:26])=[CH2:25].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([O:28][CH2:29][CH2:30][NH:31][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[C:13]([O:14][C:15](=[O:17])[CH3:16])=[C:12]([O:18][C:19](=[O:21])[CH3:20])[CH:11]=1)(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: C=C(C)C(=O)OCCN
Reactant: CC(=O)Oc1cc(C(=O)Cl)cc(OC(C)=O)c1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)c1cc(OC(C)=O)c(OC(C)=O)c(OC(C)=O)c1
Reaction time: 0.5 h

Procedure:
3,4,5-Triacetoxybenzoyl chloride (0.050 mol) was dissolved in 100 mL CH2Cl2 at 0° C. To this was added 2-aminoethyl methacrylate hydrochloride (8.28 g, 0.050 mol), followed by dropwise addition of triethylamine (14.63 mL, 0.105 mol). After 30 min, 100 mL 1N HCl was added with vigorous stirring. The organic layer was isolated, washed with saturated NaHCO3 and 50 mL 1N HCl, dried over MgSO4, and evaporated to give an oil, which crystallized rapidly after the addition of 50 mL diethyl ether. The product was isolated by filtration and vacuum dried. Yield, 17.97 g as a white solid, 88%. 1H NMR (300 MHz, CDCl3), δ1.92 (s, 3H), 2.26 (s, 6H), 2.27 (s, 3H), 3.68 (m, 2H), 4.30 (t, 2H), 5.58 (m, 1H), 6.11 (s, 1H), 6.66 (t, broad, 1H), 7.51 (s, 2H). Anal., calcd for C19H21N1O9C 56.02, H 5.20, N 3.44, found C 55.99, H 5.15, N 3.50.
Reaction SMILES: [CH3:1][C:2]([N:14]1[CH:18]=[C:17]([NH:19][C:20](=[O:26])[CH:21]([NH2:25])[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]1)([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([F:38])[CH:37]=1)[CH2:34][C:33](=O)[CH2:32][CH2:31]2>>[CH3:1][C:2]([N:14]1[CH:18]=[C:17]([NH:19][C:20](=[O:26])[C@@H:21]([NH:25][CH:33]2[CH2:32][CH2:31][C:30]3[C:35](=[C:36]([F:38])[CH:37]=[C:28]([F:27])[CH:29]=3)[CH2:34]2)[CH2:22][CH2:23][CH3:24])[N:16]=[CH:15]1)([CH3:13])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CCNCc2ccccn2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CCNCc2ccccn2)cn1

Procedure:
2-Amino-pentanoic acid (1-{1,1-dimethyl-3-[(pyridin-2-ylmethyl)-amino]-propyl}-1H-imidazol-4-yl)-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to afford the title: 525.5 m/z (M+1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=3)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:29]=1
Reactant: Fc1ccc(Oc2cccc(NCc3cccc(OC(F)(F)C(F)F)c3)c2)cc1
Reactant: FC(F)(F)C1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccc(F)cc2)c1)C(F)(F)F
Temperature: 40 °C
Yield: 80.9 %

Procedure:
The N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (612 mg, 1.5 mmol) product from EX-634C and 1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:11) to give 633 mg (81%) of the desired 3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. 1H NMR(CDCl3) δ7.35 (t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). 19F NMR (CDCl3) δ−79.2 (d, 3F), −88.5 (m, 2F), −120.33 (m, 1F), −[137.2 (dt, 2F). HRMS calcd: for C24H19F8NO3: 522.1315 [M+H]+, found: 522.1297.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].Cl[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:18][O:17][C:15]([CH2:14][C:12]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9])=[O:13])=[O:16]
Reactant: Nc1cnccc1C(=O)O
Reactant: COC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CC(=O)Nc1cnccc1C(=O)O

Procedure:
A solution of 3-aminopyridine-4-carboxylic acid (1.0 eq), methyl 2-(chlorocarbonyl)acetate (1.1 eq), and triethylamine (2.0 eq) in acetone was stirred overnight at room temperature. The solvent was removed in vacuo. The product was used without further purification. LC/MS m/z 239.2 (MH+), Rt 1.40 minutes.