Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.CO>Cl.O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:31]=[C:32]([C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[C:33]([Cl:42])=[CH:34][C:35]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(-c4ccc(F)cc4)c(Cl)cc3-c3ccnnc3)cc2F)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2cc(-c3ccc(F)cc3)c(Cl)cc2-c2ccnnc2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
5-Chloro-4-(6-chloro-4′-fluoro-4-(pyridazin-4-yl)biphenyl-3-yloxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 101, 100 mg, 0.13 mmol) was dissolved in a 4M solution of HCl in dioxane (10 mL). The reaction mixture was stirred for 18 hours at room temperature. Methanol (50 mL) was added to the reaction mixture and the suspension was concentrated in vacuo. The crude residue was purified by reverse phase semi preparative HPLC (solvent A: 0.05% formic acid in acetonitrile, solvent B: 0.05% formic acid in water; flow rate: 12.5 ml/min; gradient: 0 min 10% A, 2.5 min 10% A, 32.5 min 95% A, 37.5 min 95% A then return to initial conditions) to afford the title compound (46 mg, 60%) as a solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:11]=[N:10][C:9]2[C:4]1=[N:5][C:6]([C:31]#[N:32])=[N:7][C:8]=2[C:12]1[CH:13]=[N:14][C:15]([O:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)[CH3:34].[Na+].C(=O)C.C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[CH2:33]([N:28]1[CH2:29][CH2:30][CH:25]([CH2:24][CH2:23][O:22][C:15]2[N:14]=[CH:13][C:12]([C:8]3[N:7]=[C:6]([C:31]#[N:32])[N:5]=[C:4]4[C:9]=3[N:10]=[CH:11][N:3]4[CH3:2])=[CH:17][C:16]=2[C:18]([F:21])([F:19])[F:20])[CH2:26][CH2:27]1)[CH3:34]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cn1cnc2c(-c3cnc(OCCC4CCNCC4)c(C(F)(F)F)c3)nc(C#N)nc21
Agent: CC=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN1CCC(CCOc2ncc(-c3nc(C#N)nc4c3ncn4C)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.1 %

Procedure:
Triethylamine (2.7 mL) was added to a suspension of 9-methyl-6-{6-[2-(piperidin-4-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-9H-purine-2-carbonitrile monohydrochloride (3.0 g) in dichloroethane (60 mL) at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After the reaction mixture was ice-cooled, acetic acid (1.8 mL), sodium triacetoxyborohydride (2.7 g) were added thereto, and a solution of acetaldehyde (1.1 mL) in dichloroethane (5 mL) was added thereto. The mixture was stirred for 1 hour under ice-cooling. After a saturated aqueous NaHCO3 solution was added to the reaction mixture, extraction thereof was performed using CHCl3, and the extract was washed with saturated brine. The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was suspended in EtOH (80 mL), and the suspension was dissolved by stirring for 30 minutes while heating to reflux. The mixture was cooled to room temperature, and the precipitate was collected by filtration, whereby 6-{6-[2-(1-ethylpiperidin-4-yl)ethoxy]-5-(trifluoromethyl)pyridin-3-yl}-9-methyl-9H-purine-2-carbonitrile (1.8 g) was obtained as a crystal (heat absorption peak temperature obtained by a TG/DTA analysis: near 191° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.C(OC(=O)[NH:50][C@H:51]([CH2:59][NH2:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(C)(C)C>CN(C=O)C>[NH2:50][C@@H:51]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:59][NH:60][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CN)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)NC[C@@H](N)Cc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (0.225 g, 1.2 mmol) and HATU (0.46 g, 1.2 mmol) in DMF (10 mL) is added N-methylmorpholine (0.53 mL, 4.8 mmol) and ((S)-1-aminomethyl-2-phenyl-ethyl)-carbamic acid tert-butyl ester (0.3 g, 1.2 mmol) and the resulting yellow solution is stirred at RT for 18 h. The solvent is removed in vacuo and the residue is diluted with water (10 mL). The precipitate which forms is collected by filtration and dissolved in DCM (5 mL). TFA (1 mL) is added and the solution stirred at RT for 1 h. The solvent is removed in vacuo, and the residue is purified by reverse phase chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% TFA) to yield the title compound. [M+H]+ 321
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([OH:20])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18]O)=[CH:9][N:8]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]3[C:12]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:18][O:20]3)=[CH:9][N:8]([CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCn1cc(C(O)c2ccccc2CO)c2cc(Br)cnc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCn1cc(C2OCc3ccccc32)c2cc(Br)cnc21
Temperature: 25 °C
Yield: 83.9 %

Procedure:
2,2-Dimethyl-propionic acid 5-bromo-3-[hydroxy-(2-hydroxymethyl-phenyl)-methyl]-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (1.60 g, 3.58 mmol) was dissolved in anhydrous dichloromethane (80 ml), and the mixture was stirred at room temperature. Boron trifluoride etherate (374 ul, 2.97 mmol) was added and the mixture stirred for 20 minutes. The reaction was quenched with saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was washed with dichloromethane. The organic layers were combined, dried over magnesium sulfate, and the mixture was concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give 1.29 g (84%) of 2,2-dimethyl-propionic acid 5-bromo-3-(1,3-dihydro-isobenzofuran-1-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 429.2+431.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([N:11]=O)[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: CC(C)CCN1CCN(N=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCN1CCN(N)CC1
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A solution of N-(3-methyl-butyl)-N'-nitrosopiperazine (3 g.) in anhydrous tetrahydrofuran (30 ml). was added dropwise to a stirred suspension of lithium aluminium hydride (0.65 g.) in anhydrous tetrahydrofuran (100 ml.) under nitrogen at 50°. After 30 minutes, the mixture was cooled and worked up in the usual manner to give crude N-(3-methylbutyl)-N'-amino-piperazine (2.5 g.) used without purification in the next step.
Reaction SMILES: C(N1CCN(CC2C=CC=CC=2)CC1C(O)=O)C1C=CC=CC=1.C(N1CCN(CC2C=CC=CC=2)CC1C([N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:57]=[C:56]([CH3:58])[CH:55]=[CH:54][C:53]=2[CH3:59])[CH2:48][CH2:47]1)=O)C1C=CC=CC=1>>[CH3:59][C:53]1[CH:54]=[CH:55][C:56]([CH3:58])=[CH:57][C:52]=1[N:49]1[CH2:48][CH2:47][NH:46][CH2:51][CH2:50]1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN(Cc4ccccc4)CCN3Cc3ccccc3)CC2)c1
Agent: O=C(O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Product: Cc1ccc(C)c(N2CCNCC2)c1

Procedure:
In analogy to example 1, step 1, from 1,4-dibenzylpiperazine-2-carboxylic acid (CAS Reg. No.: [215597-67-4]) and 1-(2,5-dimethylphenyl)piperazine was prepared (1,4-dibenzyl-piperazin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone as a white foam, MS: 483.3 ([M+H]+).
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S([O:19][CH:20]([C:27]1(O)[CH2:30][N:29]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[C:35]([F:40])[C:34]=2[NH:41][C:42]2[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=2[F:49])=[O:32])[CH2:28]1)[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1)(=O)=O)C.[H-].[Na+].C(OCC)(=O)C>O1CCCC1>[O:26]1[CH2:25][CH2:24][O:23][CH:22]1[CH2:21][CH:20]1[C:27]2([CH2:30][N:29]([C:31]([C:33]3[C:34]([NH:41][C:42]4[CH:47]=[CH:46][C:45]([I:48])=[CH:44][C:43]=4[F:49])=[C:35]([F:40])[C:36]([F:39])=[CH:37][CH:38]=3)=[O:32])[CH2:28]2)[O:19]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OC(CC2OCCO2)C2(O)CN(C(=O)c3ccc(F)c(F)c3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC2(C1)OC2CC1OCCO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 95 %

Procedure:
1-[1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]-2-(1,3-dioxolan-2-yl)ethyl 2,4,6-tris(1-methylethyl)benzenesulfonate (50 mg, 0.060 mmol) was dissolved in tetrahydrofuran (1 mL) and was cooled to 0° C. Sodium hydride (60 wt % dispersion in oil; 7 mg, 0.18 mmol) was added and the mixture was stirred at 0° C. for 45 minutes. The mixture was quenched with saturated sodium bicarbonate solution and partitioned with ethyl acetate. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 50% ethyl acetate in hexanes) gave 6-{[2-(1,3-dioxolan-2-ylmethyl)-1-oxa-5-azaspiro[2.3]hex-5-yl]carbonyl}-2,3-difluoro-N-(2-fluoro-4-iodophenyl)aniline (31 mg, 0.057 mmol, 94% yield): MS (EI) for C21H18F3IN2O4: 547 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(O)Cn1ccc2cc(F)ccc21
Reaction time: 1 h
Yield: 62 %

Procedure:
A suspension of 0.55 g of sodium hydride dispersion in 75 ml of tetrahydrofuran was treated with 2 g of 5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 2.1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 24 hours and subsequently treated with 5 ml of water. The mixture was diluted with ether, washed three times with 75 ml of water each time and with 70 ml of saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 60 g of silica gel with toluene-ethyl acetate (19:1). There were obtained 1.8 g (62%) of (RS)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([C:23]([F:26])([F:25])[F:24])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:27][OH:28])=[CH:4][CH:3]=1.CC1(C)N([O])C(C)(C)CCC1.[N+]([O-])([O-])=O.[Na+].O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:27]=[O:28])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([C:23]([F:25])([F:24])[F:26])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CO)c23)c(C(F)(F)F)n1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 64 h
Yield: 67.8 %

Procedure:
A mixture of {9-chloro-1-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}methanol (500 mg, 1.21 mmol), 2,2,6,6-tetramethylpiperidine 1-oxyl (18.9 mg, 0.12 mmol) and sodium nitrate (33.4 mg, 0.484 mmol) in acetic acid (10 mL) was stirred at room temperature and ambient pressure for 64 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound (336.3 mg, 0.82 mmol, 68%) as a pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[C:8]=2[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O/[N:45]=[C:46](/[C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]2[CH2:56][CH:55]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:54]2)=[CH:50][CH:49]=1)\[NH2:47].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(#N)C>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:14][N:47]=[C:46]([C:48]4[CH:49]=[CH:50][C:51]([CH2:52][N:53]5[CH2:54][CH:55]([C:57]([O:59][C:60]([CH3:61])([CH3:63])[CH3:62])=[O:58])[CH2:56]5)=[CH:64][CH:65]=4)[N:45]=3)[C:8]=2[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1CCC(F)(F)F
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: On1nnc2ccccc21
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4CCC(F)(F)F)n3)cc2)C1
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 5-phenyl-4-(3,3,3-trifluoropropyl)isoxazole-3-carboxylic acid (5 mg, 0.018 mmol), HOBt (4.83 mg, 0.032 mmol) and diisopropylethylamine (12.3 μL, 0.070 mmol) in acetonitrile (0.5 mL) was added EDC (7.90 mg, 0.041 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 5.35 mg, 0.018 mmol). The reaction mixture was stirred at 23° C. for 2.5 h. The mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated and dissolved in acetonitrile (0.5 mL). A 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (35 μL, 0.035 mmol) was added, and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (3 mL), washed with water (1 mL), washed with a saturated aqueous solution of sodium carbonate (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification on a preparative TLC plate with hexanes/ethyl acetate (7/3) afforded tert-butyl 1-(4-(5-(5-phenyl-4-(3,3,3-trifluoropropyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([I:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH:19](I)([CH3:21])[CH3:20]>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([I:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:12][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)I
Reactant: COc1cc(I)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(I)cc(OC)c1OC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a suspension of 2,6-dimethoxy-4-iodophenol (1.0 g) and potassium carbonate (938 mg) in DMF (10 mL) was added isopropyl iodide (507 mL). The mixture was stirred at 60° C. for 3 hours and evaporated. Ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was applied to a column of silica gel using hexane-ethyl acetate (5:1) as an eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:25])([CH3:24])[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:25])([CH3:24])[CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:21])[F:23])=[CH:15][CH:14]=2)[C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(C)CNCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: Clc1ncccn1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(C)(C)CN(Cc2ccc(OC(F)(F)F)cc2)c2ncccn2)cc1
Yield: 88.1 %

Procedure:
Condensation N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]amine (250 mg; 0.71 mmol) with 2-chloro-pyrimidine (85 mg; 0.74 mmol) as per general procedure E (2 eq DIEA, 210C, 14 hr) afforded N-[2-(4-methoxyphenyl)-2-methylpropyl]-N-[4-(trifluoromethoxy)benzyl]pyrimidin-2-amine (270 mg; 88% yield). MS: m/z 432 (M+1).
Reaction SMILES: C([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])(OC(C)(C)C)=O.F[C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26]>[OH-].[Na+].C(O)C.Cl.C(O)(=O)C>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:19]1[CH:20]=[C:21]([CH3:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26])[C:15]([OH:17])=[O:16]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(NCCCC[C@H](N)C(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
A mixture of 2.37 g (10 mmol) of Nα -BOC-L-lysine and 1.65 g (11.0 mmol) of 3-fluoro-4-nitrotoluene in 10 mL of 1N NaOH and 10 mL of ethanol were heated at reflux for 48 hours, then cooled to room temperature. A precipitate was filtered off and discarded. Removal of the solvent/n vacuo gave an oil which was dissolved in 50 % ethanol/3M NH3 and taken to dryness. The residue was dissolved in 12 mL of 4N HCl in 33% acetic acid and stirred for four hours, then concentrated to dryness and purified by flash chromatography (eluting with 12:1:1 acetonitrile/water/HOAc). The resulting oil was recrystallized from water/methanol to afford 470 mg (42% yield) of the title product as bright orange prisms.: mp 234°-235° (dec.); MS M/Z (DCl/NH3): 282 [M+H]+ ; 1H NMR (300 MHz, D2O) δ: 1.1-1.45 (m, 6H), 2.78 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.0 Hz, 1H), 5.88 (d, J=7.8 Hz, 1H), 6.07 (s, 1H), 7.32 (d, J=7.8 Hz, 1H). 13C NMR (75.5 MHz, D2O) δ: 185.73, 151.31,148.37, 131.02, 119.60, 116.09, 58.83, 45.20, 37.87, 31.19, 25.86; Analysis calc'd for C13H19N3O4 : C, 55.51;H, 6.81;N, 14.94; found: C, 55.25;H, 6.94; N, 14.75.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:18][C:19]([F:22])([F:21])[F:20])[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[C:23]([NH:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:18][C:19]([F:20])([F:21])[F:22])[CH2:4][CH2:3][CH2:2][O:1][C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:25])[CH3:24])=[CH:28][CH:29]=2)=[CH:7][C:8]=1[C:14]([F:16])([F:15])[F:17])#[N:11]
Reactant: N#Cc1ccc(N(CCCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)Nc1ccc(O)cc1
Product: CC(=O)Nc1ccc(OCCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(3-hydroxypropyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-acetamidophenol: MS (APCI) m/z 460 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[C:20](#[N:24])[CH:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:21]([CH3:23])([CH3:22])[C:20]#[N:24])=[CH:13][CH:14]=1
Reactant: COc1ccc(F)cc1
Reactant: CC(C)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C#N)cc1
Yield: 52 %

Procedure:
Add potassium bis(trimethylsilyl)amide (39.90 g, 200 mmol) to a stirred solution of 4-fluoroanisole (15.0 mL, 133 mmol), isobutyronitrile (49.0 mL, 539 mmol) and anhydrous tetrahydrofuran (150 mL). Heat the reaction to reflux under nitrogen for 72 h. Cool the reaction to room temperature, pour it into 1 N hydrochloric acid (300 mL), and extract with diethyl ether (3×100 mL). Wash the diethyl ether extracts with brine (100 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield 12.13 g (52%) of 2-(4-methoxy-phenyl)-2-methyl-propionitrile: TLC: Rf in 10% ethyl acetate/hexanes: 0.30; 1H NMR (CDCl3): 7.40-7.37 (m, 2H), 6.92-6.90 (m, 2H), 3.81 (s, 3H), 1.70 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:11].CC(C)([O-])C.[K+].[Br:18][C:19](Br)([F:21])[F:20].O>CN1CCN(C)C1=O>[Br:18][C:19]([F:21])([F:20])[O:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: FC(F)(Br)Br
Reactant: COc1cccc(O)c1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COc1cccc(OC(F)(F)Br)c1OC
Temperature: 55 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
To a solution of 5.0 g of 2,3-dimethoxy phenol in 1,3-dimethyl-2-imidazolidinone (65 ml) was added 7.28 g of potassium tert-butoxide, and was added dropwise a solution of 41.5 g of dibromo difluoromethane in 1,3-dimethyl-2-imidazolidinone (20 ml) over 30 minutes. The solution was stirred at 55° C. for 3 hours, and then water was added and the resulting mixture was extracted with Et2O. The organic layer was sequentially washed with 1 mol/L hydrochloric acid, water, and saturated brine, dried over MgSO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: EtOAc/n-hexane=1/9 to 1/4; v/v) to obtain 2.21 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[C:12]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:35](=O)([O-])[O-]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1[C:12]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]([CH3:35])[C:18](=[O:21])[C:17]([CH3:23])([CH3:22])[NH:16]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccccc1)NC(=O)C(C)(C)N2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccccc1)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
A mixture of 8-benzoyloxymethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 1-3, 42.9 mg, 0.099 mmol), methyliodide (30.7 μL, 0.49 mmol), and cessium carbonate (89.0 mg, 0.27 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (100 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (35.0 mg) as a colorless amorphous product. (Yield 79%)