Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11](I)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1.[C:27]([NH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:34]2[CH:35]=[CH:36][C:31]([NH:30][C:27](=[O:29])[CH3:28])=[CH:32][CH:33]=2)=[N:10][C:9]=1[C:14]1[N:18]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[N:16][N:15]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2nc(-c3nncn3COCC[Si](C)(C)C)c(-c3ccccc3Cl)o2)cc1
Yield: 89.1 %

Procedure:
A mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (0.11 g, 0.22 mmol), tetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.043 mmol), (4-acetamidophenyl)boronic acid (0.115 g, 0.64 mmol) and cesium carbonate (0.46 g, 1.40 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was sealed in a tube and subjected to microwave irradiation at 150° C. for 60 min. The reaction mixture was concentrated and the residue was purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]phenyl}acetamide (0.100 g, 91%). LCMS (AA): m/z=510 (M+H).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)C=C.CN(C)[C:18]1[CH:23]=CC=C[CH:19]=1>>[CH2:23]([C:15]1[CH:14]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:4])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:18]=[CH2:19]
Reactant: C=CCOc1ccc(C(=O)OCC)cc1
Reactant: CN(C)c1ccccc1
Product: C=CCc1cc(C(=O)OCC)ccc1O
Temperature: 25 °C

Procedure:
A mixture of 82.3 g (0.899 mole) ethyl 4-allyloxybenzoate in 100 ml N,N-dimethylaniline was stirred under nitrogen while heating at reflux for 2 days. The resulting mixture was cooled to room temperature, the solvent distilled in vacuo, the residue taken up in ethyl ether, washed three times with 1N hydrochloric acid and extracted with 1N sodium hydroxide solution. The alkaline extract was acidified to pH 3.0, extracted with ethyl ether and the extracts dried (MgSO4). Evaporation of solvent provided 47.1 g of the desired product as a solid, TLC with 1.5:1 isopropyl ether/hexane gave one spot, Rf 0.2.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5](Cl)[N:4]=1.[CH2:20]([OH:22])[CH3:21]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)=[C:5]([O:22][CH2:20][CH3:21])[N:4]=1
Reactant: CCO
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na]
Product: CCOc1nc(N)nc2c1ncn2[C@H]1C=C[C@@H](CO)C1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A flask was charged with ethanol (33 ml) and sodium (0.172 g, 7.5 mmol). After all of the sodium had dissolved (±)-cis-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.40 g, 1.5 mmol) from Example 4 was added and the solution was brought to reflux for 0.5 hours. The solution was allowed to cool to room temperature before neutralization with 1.0 N HC1. The solution was then concentrated and the residue partitioned between chloroform and water. The organic layer was dried with MgSO4, filtered and concentrated. The residues were then placed on a silica gel column and eluted with 2% methanol in chloroform to yield a yellow glass (0.28 g, 67.8%).
Reaction SMILES: C(OCC)(=O)C.[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-:21]#[N:22].[K+]>O>[OH:20][CH:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:21]#[N:22]
Reactant: [C-]#N
Reactant: O=CCCCCCCc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC(O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A two-phase mixture of ethyl acetate (30 mL) and water (35 mL) containing 7-phenylheptanal (5.2 g) and KCN (7.1 g) was stirred vigorously at room temperature for 24 h. The layers were separated and the aqueous phase was washed with water, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyloctanenitrile as an oil.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O1CCOCC1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>[OH-].[Na+]>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([N:2]([CH3:1])[C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)O)cc1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
N-Methyl-L-phenylalanine (500 mg, 2.79 mmol) was dissolved in 1N NaOH (6 mL). Dioxane (9 mL)) was added, followed by p-toluenesulfonyl chloride (532 mg, 2.79 mmol) and the mixture was vigorously stirred for 1 hr. The volatiles were removed in vacuo and the residue was dissolved in water (30 mL) and washed with Et2O (2×30 mL) before making acidic with 1N HCl. The mixture was extracted with CHCl (3×30 mL) and the extracts were evaporated in vacuo to give N-(toluene-4-sulfonyl)-N-methylphenylalanine as a solid (424 mg, 45%).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:23]([O:25]CC)=[O:24])([CH3:22])[CH3:21])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)C.[OH-].[K+].Cl>C(O)C.O>[C:23]([C:20]([CH3:22])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]1([CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)([OH:25])=[O:24]
Reactant: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC1(CCCCC(C)(C)C(=O)O)SCCCS1)C(=O)O
Yield: 95.5 %

Procedure:
A solution of 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (870 mg, 1.89 mmol) and potassium hydroxide (85%, 750 mg, 11.33 mmol) in ethanol (16 mL) and water (4 mL) was heated under reflux for 3 h. The reaction mixture was diluted with water (100 mL) and acidified to pH 4 with 1 N HCl (8 mL). The emulsion was extracted with dichloromethane (3×75 mL). The combined organic phases were washed with water (50 mL), dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-carboxy-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid (730 mg, 95%) as a viscous, yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 2.80 (m, 4H), 1.94 (m, 2H), 1.85 (m, 4H), 1.56 (m, 4H), 1.41 (m, 4H), 1.30 (m, 4H), 1.19 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 185.08, 53.36, 42.28, 40.52, 38.27, 26.18, 25.69, 25.23, 25.11, 24.73. HRMS (LSIMS, nba): Calcd. for C20H37O4S2 (MH+): 405.2133, found: 405.2115.
Reaction SMILES: [CH3:1][C:2]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[C:12]([NH:14][C:15]([NH2:17])=[NH:16])#[N:13]>C(OCCOCCO)C>[NH2:17][C:15]1[N:14]=[C:12]([NH2:13])[C:9]2[CH2:10][CH:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:6][CH2:7][C:8]=2[N:16]=1
Reactant: N#CNC(=N)N
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: CCOCCOCCO
Product: CC(C)(C)C1CCc2nc(N)nc(N)c2C1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
A reaction vessel equipped with a Dean Stark trap was charged with 11.8 grams (0.075 mole) of 4-(1,1-dimethylethyl)cyclohexanone and 4.2 grams (0.050 mole) of cyanoguanidine in 20 mL of 2-(2-ethoxyethoxy)ethanol. The mixture was heated incrementally at 80° C., 100° C., 140° C. and 160° C., the latter where it was stirred for about 18 hours. The reaction mixture was then cooled to ambient temperature, where it solidified. The reaction mixture was triturated with 30 mL of diethyl ether, and the resultant solid was collected by filtration. The solid was washed several times with diethyl ether, yielding, when dried, 4.5 grams of 2,4-diamino-6-(1,1-dimethylethyl)-5,6,7,8-tetrahydroquinazoline, mp>250° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:4]N([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C(C)=C1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C.[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C@H:55]([CH2:65][OH:66])[C:54]([CH:67]([CH3:69])[CH3:68])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]>>[CH2:35]([O:38][N:39]([C@H:52]1[CH2:57][N:56]([C:58]([O:60][C:61]([CH3:62])([CH3:63])[CH3:64])=[O:59])[C@H:55]([C:65]([OH:4])=[O:66])[C:54]([CH:67]([CH3:69])[CH3:68])=[CH:53]1)[S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N+:49]([O-:51])=[O:50])(=[O:42])=[O:41])[CH:36]=[CH2:37]
Reactant: C=CCON([C@@H]1C=C(C(C)C)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@@H]1C=C(C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C(C)C)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 87.76 %

Procedure:
((2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-isopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (0.595 g, 87.76%) was prepared a similar manner as described in Intermediate 82 as a yellow oil, using (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(hydroxymethyl)-3-isopropyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 92, 660 mg, 1.29 mmol) as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:10][C:3]=12.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:9]([CH:11]3[CH2:13][CH2:12]3)=[N:10][C:3]=12
Reactant: Clc1ccnc2[nH]c(C3CC3)nc12
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(Cn3c(C4CC4)nc4c(Cl)ccnc43)cc2COc2cc(F)ccc21
Yield: 54.2 %

Procedure:
Using 7-chloro-2-cyclopropyl-3H-imidazo[4,5-b]pyridine (EP1988091, 81 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (107 mg, 54%) was obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>O1CCCC1>[CH3:7][O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)CCc1ccc(-c2ccc(OC)nc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CCC(=O)O)cc2)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of lithium aluminum hydride (2.28 g) in tetrahydrofuran (120 mL), the compound obtained from step c above (8 g) in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched carefully with saturated ammonium chloride solution, filtered through celite, and washed with ethyl acetate. The organic layers were separated, washed with brine, and dried over anhydrous sodium sulfate, and solvents were evaporated under reduced pressure. The crude product was purified by silica gel flash column chromatography using 20% to 30% ethyl acetate in hexane to get the title compound as a white crystalline solid (5.1 g).
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClC(Cl)(Cl)C1O[N:16]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(Cl)Cl>[CH3:11][C:2]([NH:12][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(CC(C)(C)N)cc1
Reactant: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(CC(C)(C)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
2.40 g (14.7 mmol) of separately prepared 2-methyl-1-p-tolylpropan-2-amine was dissolved in 20 mL of methylene chloride, and 2.60 g (10.0 mmol) of separately prepared t-butyl 3-(trichloromethyl)-1,2-oxaziridine-2-carboxylate in 10 mL of methylene chloride was added under cooling with ice. The reaction slution was stirred under cooling with ice for 30 minutes and at room temperature for 1 hour, and the methylene chloride was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (100:0 to 0:100) as the eluent to give 1.61 g of the desired product as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1.C1(=O)O[CH2:25][CH2:24][O:23]1>CN(C)C=O>[Cl:7][C:8]1[CH:21]=[CH:20][C:11]2[C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH2:24][OH:23])=[CH:15][C:13]=3[O:14][C:10]=2[CH:9]=1
Reactant: Oc1ccc2c(c1)oc1cc(Cl)ccc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccc2c(c1)oc1cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
83 g (0.6 mole) of potassium carbonate were added to a solution of 262 g (1.2 moles) of 7-chlorodibenzofuran-3-ol in 600 ml of dry dimethylformamide, and a solution of 212 g (2.55 moles) of ethylene carbonate in 300 ml of dimethylformamide was then added dropwise at 100° C. in the course of 90 minutes. The mixture was stirred at 120° C. for 8 hours and filtered off with suction at 100° C., and the filtrate was concentrated. The residue was dissolved in 2.5 l of ethyl acetate, the solution was washed three times with 300 ml of water each time, the organic layer was dried, decolorized with 10 g of animal charcoal and concentrated to 500 ml and the concentrate was cooled to 10° C. The precipitate was filtered off with suction and washed, at +5° C., with 60 ml of methanol, 50 ml of ether and 200 ml of petroleum ether in succession, and dried. 225 g of 2-(7-chlorodibenzofuran-3-oxy)-ethanol of melting point 118°-120° C. were obtained; yield: 71.4% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].[BH4-].[Na+]>>[CH2:13]([N:16]([CH2:17][CH2:18][CH3:19])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: CCCNCCC
Reactant: O=C1CCc2cccc(F)c2C1
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CCC)C1CCc2cccc(F)c2C1
Yield: 33 %

Procedure:
8-Fluoro-2-tetralone (2.60 gm, 15.8 mMol) was reacted with dipropylamine (3.3 mL, 33 mMol) and sodium borohydride (1.5 gm) as described in Example 1 to give the title compound as a colorless oil (1.3 gm, 33%). The hydrochloride salt was formed and crystallization (ethanol/diethyl ether) gave colorless crystals (m.p.=164° C.).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([F:23])[CH:22]=1>>[N+:13]([C:10]1[CH:11]=[CH:12][C:2]([O:24][C:19]2[CH:18]=[C:17]([F:16])[CH:22]=[C:21]([F:23])[CH:20]=2)=[C:3]([CH:9]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])([O-:15])=[O:14]
Reactant: Oc1cc(F)cc(F)c1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Cl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1cc(F)cc(F)c1
Yield: 94.7 %

Procedure:
Using the method described in Example 21.2, ethyl 2-chloro-5-nitrobenzoate (0.6 g) and 3,5-difluorophenol (0.34 g) were combined to provide 0.8 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:52][NH:53][C:54]1[C:55]([NH2:60])=[CH:56][CH:57]=[CH:58][CH:59]=1>CN(C=O)C>[NH2:60][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=1[N:53]([CH3:52])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[N:13][C:5]=1[O:4][C:3]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=1[Cl:1]
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: CNc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl)c1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (50 mg, 0.18 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (2 mL) was added N-ethyldiisopropylamine (116 mg, 154 μL, 0.90 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (82 mg, 0.22 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt for 30 min. After addition of N-methyl-benzene-1,2-diamine (26.9 mg, 0.22 mmol, 1.2 equiv; [CAS RN 4760-34-3]) stirring was continued at rt for 90 min. Removal of the solvent under reduced pressure and purification by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate afforded 33 mg (47%) of the title compound as a white solid. MS (ISP): 388.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([F:34])[CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:57][CH2:58][C:59]([CH3:68])([CH3:67])[CH2:60][NH:61][C:62](=[O:66])[C:63]([NH2:65])=[O:64].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:57][CH2:58][C:59]([CH3:68])([CH3:67])[CH2:60][NH:61][C:62](=[O:66])[C:63]([NH2:65])=[O:64])=[O:30])=[C:27]([F:34])[CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1F
Reactant: CC(C)(CN)CNC(=O)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)C(N)=O)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-2-fluorobenzoic acid (10 mg) and TBTU (7.74 mg) in DMF (1 mL) was added N1-(3-amino-2,2-dimethylpropyl)oxalamide (4.18 mg) and DIPEA (0.018 mL). The mixture was stirred at room temperature for 2 hours. The product was isolated by using preparative HPLC system.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]3)[C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]3)[C:13](=[O:18])[C:14]([F:16])([F:15])[F:17])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN(Cc2cc3c(cn2)OCCO3)C(=O)C(F)(F)F)C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N(Cc1cc2c(cn1)OCCO2)CC1CCCNC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 44.6 %

Procedure:
To a solution of 0.43 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)methyl)piperidine-1-carboxylate in 3 mL of chloroform, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour 40 minutes. The solvent was distilled off under reduced pressure. The resultant residue was charged with chloroform and water, and adjusted to pH 8.0 with an aqueous sodium hydrogen carbonate solution and a 20% aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.15 g of N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)-2,2,2-trifluoro-N-(piperidin-3-ylmethyl)acetamide as a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[F:15][CH:16]([F:37])[CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[F:15][CH:16]([F:37])[CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)=[O:20]
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(F)F)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)NCC(F)F)cc2)n1

Procedure:
Method as described for example 49 using (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) and 1-(2,2-difluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 20). Purified by prep HPLC at high pH to afford the title compound. (68 mg, 38%).