Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.C1COCC1.C1COCC1.[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=2)[CH:21]([CH2:37][CH3:38])[C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:26]=2)[CH:21]([CH2:37][CH3:38])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCC1C(=O)N(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCC1CN(Cc2ccccc2)CCN1c1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 4 h
Yield: 47.3 %

Procedure:
At 0° C., 5 ml of 1 M borane-THF solution was added dropwise to 30 ml of anhydrous THF solution containing 1.47 g of 4-(4-benzyl-2-ethyl-3-oxopiperazin-1-yl)-2-trifluoromethylbenzonitrile synthesized in Reference Example 5-1, and the mixture was stirred for 4 hours. After addition of 10 ml of methanol and 38 ml of 1 N hydrochloric acid to the mixture with stirring, the reaction solution was evaporated under reduced pressure, the resulting residue was neutralized with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, the organic layer was washed and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography, and 0.67 g of the title compound was obtained from hexane-ethyl acetate (5:1, v/v) eluate as yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][C:4]=1[CH3:11].[Cl:12]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:12])=[CH:5][C:4]=1[CH3:11]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccc(CO)cc1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of (4-methoxy-3-methylphenyl)methanol (2.31g, 15.18mmoles, 1eq) in anhydrous CH2Cl2(50ml, 0.3M) was added hexachloroethane (3.59g, 15.18mmoles, 1eq) and triphenylphosphine (3.98g, 15.18mmoles, 1eq). This mixture was stirred at room temperature overnight at which point the reaction was transferred to a separatory funnel and washed with H2O, brine, dried over Na2SO4, filtered, concentrated in vacuo and filtered through a plug of silica gel (30% EtOAc/Hexanes) to yield 2.59g (100%) of product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[NH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[CH2:42][CH2:43][NH2:44].C(N(CC)CC)C>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[NH:14][N:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([NH:44][CH2:43][CH2:42][C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[Cl:39])=[O:6]
Reactant: NCCc1ccccc1Cl
Reactant: O=C(O)c1cc(-n2cn[nH]c2=O)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1Cl)c1cc(-n2cn[nH]c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
To a solution of 2-chloro-5-(5-oxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid (0.028 g, 0.117 mmol) in anhydrous dimethyl fomamide (DMF) (4 mL) was added 1-hydroxybenzotriazole (0.018 g, 0.14 mmol). After stirring at room temperature for 10 minutes, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.025 g, 0.13 mmol) was added. After stirring at room temperature for 30 minutes, 2-chlorophenethylamine (0.018 g, 0.12 mmol) and triethylamine (0.012 g, 0.12 mmol) were added and the mixture stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed sequentially with water and brine, and dried over sodium sulfate. Removal of solvent in vacuo followed by purification by reverse phase HPLC yielded 0.042 g (10%) of the title compound as a colorless solid. 1H NMR (300 MHz, CDCl3) δ (m, 2H), 3.45 (m, 2H), 7.25 (m, 2H), 7.35 (m, 2H), 7.60 (d, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.78 (s, 1H), 8.43 (s, 1H) and 8.64 (m, 1H). Mass Spectrum (M−H) 3:1 Ratio of 375 and 377.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:11]=1.COC1C=CC2C=C(B(O)O)SC=2C=1.Br[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[N+:35]([O-:37])=[O:36]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=3[N+:35]([O-:37])=[O:36])[S:8][C:7]=2[CH:11]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: COc1ccc2ccsc2c1
Agent: COc1ccc2cc(B(O)O)sc2c1
Product: COc1ccc(-c2cc3ccc(OC)cc3s2)c([N+](=O)[O-])c1

Procedure:
Synthesized from 6-methoxybenzo[b]thiophene according to an analogous synthetic method to Preparation Example 78, (6-methoxybenzo[b]thiophen-2-yl)boronic acid (3.2 g) and 4-bromo-3-nitroanisole (3.4 g) were used according to an analogous synthetic method to Preparation Example 79 to provide 6-methoxy-2-(4-methoxy-2-nitrophenyl)benzo[b]thiophene (1.7 g). Synthesized from this compound (1.9 g) according to an analogous synthetic method to Example 22, the title compound (1.6 g) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.C(O)(C)C.[Pd]>[N:16]1[CH:15]=[C:14]([CH2:13][N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=3)[CH:8]=[CH:9]2)[CH:19]=[N:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc2ccn(Cc3cncnc3)c2c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1ccc2ccn(Cc3cncnc3)c2c1
Reaction time: 2 h

Procedure:
6-Nitro-1-pyrimidin-5-ylmethyl-1H-indole (4.1 g, 16.1 mmol) was dissolved in 100 mL of THF and 100 mL of isopropanol. Pd/C (2 g) was added and the mixture was stirred under an H2-atmosphere (balloon) for 2 hours. The mixture was filtered over Celite and washed with ethyl acetate affording the title compound after concentration (3.5 g, 15.6 mmol, 97%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]([OH:25])[C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[NH4+].[Cl-]>C1COCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]([O:25][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(O)c2cccc(F)c2F)C1
Reactant: CCOC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(c1cccc(F)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a suspension of NaH (3.5 g, 88.4 mmol) in THF (100 mL) at 0-5° C. was added dropwise a solution of (R)-tert-butyl 3-((2,3-difluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (9.6 g, 29.5 mmol) in THF (50 mL), the reaction mixture was stirred for 1 h at rt. A solution of ethyl bromoacetate (14.7 g, 88.4 mmol) in THF (50 mL) was added dropwise to the above mixture, and then refluxed for 3-5 h. The reaction mixture was poured into saturated aqueous NH4Cl, then extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford (3R)-tert-butyl 3-((2,3-difluorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (9.5 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 7.22 (m, 1H), 7.08 (m, 2H), 4.62 (d, 2H), 4.33 (d, 2H), 4.18 (q, 3H), 3.95 (m, 4H), 3.82 (d, 2H), 2.77 (m, 4H), 1.88 (m, 3H), 1.44 (s, 9H), 1.26 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:2]1[N:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: Nc1ncc([N+](=O)[O-])cc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc(N)c(C(=O)NCc2ccc(Oc3ccccc3)s2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
2-Amino-5-nitro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (74 mg, 0.20 mmol) described in Preparation Example A+-9, an iron powder (56 mg, 1.0 mmol) and ammonium chloride (21 mg, 0.40 mmol) were suspended in a solvent mixture of ethanol (2 mL) and water (0.5 mL), the solution was stirred at 60° C. for 3 hours, then, it was stirred at 90° C. for 6 hours. The reaction solution was cooled to room temperature, then, it was filtered through Celite pad. The filtrate was evaporated in vacuo, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water:mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (54.4 mg) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([CH:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:21]O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[CH3:16][C:15]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:8]([C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:9][N:21]=1
Reactant: NO
Reactant: COC(=O)C(C(C)=O)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc([N+](=O)[O-])cc1
Temperature: 115 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
Methyl 2-(4-nitrobenzoyl)-3-oxobutanoate (20.0 g, 75.47 mmol) was dissolved in acetic acid (70 mL), and followed by adding hydroxylamine hydrochloride (5.10 g, 73.27 mmol). The reaction was stirred at 115° C. for 2 hours. After cooling the reaction to the RT, 400 mL saturated NaHCO3 was added into the solution and extracted by ethyl acetate for 3 times. The combined organic layer was washed by brine and dried over Na2SO4, and removed under the vacuum. The crude product was further purified by flash chromatography using EA/Hexane=1:9 to give methyl 3-methyl-5-(4-nitrophenyl)isoxazole-4-carboxylate (16.4 g, 83% yield). MS m/z 263.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1cccc(CN)c1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1cccc(CNc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-methoxy-benzylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.95 (t, 1H), 7.65 (d, 1H), 7.25 (t, 1H), 7.00-6.85 (4H), 6.82 (dd, 1H), 6.19 (s, 1H), 4.50 (d, 2H), 3.92 (t, 2H), 3.82 (s, 3H), 3.74 (s, 3H) and 2.92 (t, 2H); MS (ESI) (M+H)+ 364.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.B.Cl>C1COCC1>[CH2:1]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])[P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)C(CCCCNC(=O)c1ccccc1)P(=O)(OCC)OCC
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(CCCCNCc1ccccc1)P(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
A solution of tetraethyl N-benzoyl-5-aminopentane-1,1-bisphosphonate (0.63 g, 1.36 mmol) in THF (3.4 mL) was cooled to 0° C., and borane methylsulfide (0.34 ml, 3.4 mmol) was added via syringe. The reaction was stirred at 0° C. for 20 minutes, then warmed to 65° C. for 2.5 hours. The reaction mixture was cooled to 0° C. and 6N HCl (4.0 ml) was added carefully. The solvent was removed in vacuo, and the residue was concentrated repeatedly from methanol (2×5 mL). The residue was dissolved in water (10 ml) and extracted with diethyl ether (3×5 ml). The aqueous layer was made basic to phenolphthalein with solid KOH and saturated with NaCl. The product was extracted into dichloromethane (5×20 ml), dried (Na2SO4) and concentrated to give the title compound (0.28 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=1.[C-:27]#[N:28].[K+]>O.C(O)C.O1CCCC1>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10]([CH2:9][C:7]3[N:8]=[C:3]([CH2:2][C:27]#[N:28])[CH:4]=[CH:5][CH:6]=3)=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:12]2)=[CH:17][CH:16]=1
Reactant: [C-]#N
Reactant: COc1ccc2c(Cc3cccc(CBr)n3)c(-c3ccccc3)[nH]c2c1
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(CC#N)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 88.3 %

Procedure:
To a solution of 3-[6-(bromomethyl)pyridin-2-ylmethyl]-6-methoxy-2-phenyl-1H-indole (1.37 g) in water/ethanol/tetrahydrofuran (4 mL/16 mL/4 mL) was added potassium cyanide (263 mg), and the mixture was stirred at 80° C. for 13.5 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, followed by extraction with dichloromethane. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.05 g). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 3.95 (2H, s), 4.39 (2H, s), 6.76 (1H, dd, J=2.3, 8.5 Hz), 6.91 (1H, d, J=2.3 Hz), 7.04 (1H, d, J=7.8 Hz), 7.23 (1H, d, J=7.5 Hz), 7.30-7.39 (2H, m), 7.39-7.49 (2H, m), 7.50-7.61 (3H, m), 8.05 (1H, br s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18]C(=O)OCC4C=CC=CC=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:29])[CH:3]=1.I[Si](C)(C)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Agent: C[Si](C)(C)I
Solvent: CO
Product: Cc1cc(Cl)ccc1-c1cccc2c1OC(CN)C2

Procedure:
The title compound was prepared (0.224 g, 74%) following the general procedure of Example 158 as a white solid, hydrochloride salt from (−)-benzyl {[7-(4-chloro-2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.40 g, 0.981 mmol) and iodotrimethylsilane (0.785 g, 3.92 mmol). [α]D25=−13.0 (c 10.0 in methanol); mp 190-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:4]([CH3:16])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[S:24]([CH3:23])(=[O:26])=[O:25])=[C:4]([CH3:16])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Cl)ccc1NCc1cccnc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1N(Cc1cccnc1)S(C)(=O)=O
Temperature: 25 °C

Procedure:
A 2.4 g. portion of 3-(4-chloro-2-methylphenylaminomethyl)pyridine was dissolved in 15 ml. of dichloromethane, and 2.1 g. of potassium carbonate and 2 ml. of methanesulfonyl chloride were added. The mixture was stirred at ambient temperature for several days, and then under reflux for another day. It was then cooled and diluted with 20 ml. of aqueous sodium bicarbonate and 5 ml. of 2N sodium hydroxide, 20 ml. of dichloromethane was added, and the organic layer was washed with aqueous sodium bicarbonate, dried and evaporated to an oil. The oil was dissolved in dichloromethane and chromatographed over silica gel, eluting first with dichloromethane and then with dichloromethane:ethyl acetate. The product-containing fractions were combined to obtain 1.8 g. of the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([OH:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22][C:23]([F:26])([F:25])[F:24])[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.[CH3:43][CH:44](Cl)[O:45]C(Cl)=O>O1CCCC1>[C:44]([O:27][C@:14]([C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][C:23]([F:25])([F:26])[F:24])(=[O:45])[CH3:43]
Reactant: CC(Cl)OC(=O)Cl
Reactant: OC(Cc1ccccc1SC(F)(F)F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)O[C@@](Cc1ccccc1SC(F)(F)F)(c1ccccc1)[C@H]1CNCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-benzyl-morpholin-2-yl)-1-phenyl-2-(2-trifluoromethylsulfanyl-phenyl)-ethanol (218 mg g, 1 equiv.) and solid supported Hunig's base (available from Argonaut, 1 g, 5 equiv.) in dry tetrahydrofuran (4 mL) at 0° C. under nitrogen atmosphere was added ACE-Cl (502 μL, 10 equiv.). The reaction mixture was left to warm to room temperature for 48 hours. All volatiles were evaporated under vacuum, and the resulting solid was taken-up with methanol (50 mL) and stirred at room temperature overnight. The solution was filtered through acid ion exchange column and the required fractions evaporated to dryness. The resulting solid was purified via preparative HPLC to give 62 mg of the title compound as a colourless oil. 1H NMR (300 MHz, CDCl3) δ: 2.01 (s, 3H), 2.43-2.47 (m, 1H), 2.63-2.70 (m, 1H), 2.81-2.94 (m, 2H), 3.24 (d, 1H, J=13.57 Hz), 3.85-3.96 (m, 2H), 4.01-4.05 (m, 1H), 4.09-4.13 (m, 1H), 4.45 (bs, 4H), 6.90-6.93 (m, 1H), 7.13-7.26 (m, 7H), 7.55-7.58 (m, 1H) ppm. LCMS (12 minute method) [M+H]+=384 @ Rt 5.13 min. single peak.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7].[CH3:16][NH2:17]>C(O)C>[F:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=1)[C:6]([NH:5][CH2:4][C:3](=[O:15])[NH:17][CH3:16])=[O:7]
Reactant: COC(=O)CNC(=O)c1cncc(F)c1
Reactant: CN
Solvent: CCO
Product: CNC(=O)CNC(=O)c1cncc(F)c1
Yield: 71.4 %

Procedure:
To a solution of [(5-fluoropyridine-3-carbonyl)-amino]-acetic acid methyl ester (2.96 g, 14.0 mmol) in ethanol (15 mL) was added methylamine (1.5 g, 33 wt % solution in ethanol, 70 mmol). This clear solution was then immediately put onto a 55° C. heating mantle for 10 min at which time the product had precipitated out of solution. The mixture was filtered in vacuo and the precipitate was washed with ethanol. The filtrate was concentrated and recrystallized from hot ethanol. This process was repeated again to give a white fluffy material (2.11 g, 72%): mp 201-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.10 (m, 1H), 8.93 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.10 (m, 1H), 7.95 (br s, 1H), 3.86 (d, J=5.8 Hz, 2H), 2.61 (d, J=4.4 Hz, 3H); ESIMS m/z 212 (M+1), m/z 210 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[C:13]3CN(C)C[CH2:17][N:12]3[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.N[C:21]1N=CC=CN=1.BrC1C(=O)N(C)N=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:19]=[CH:13][N:12]=[CH:17][N:11]=2)[C:5](=[O:8])[N:6]([CH3:21])[N:7]=1
Reactant: CN1CCn2nc(Nc3cc(Cl)n[nH]c3=O)cc2C1
Reactant: Nc1ncccn1
Agent: Cn1nc(Cl)cc(Br)c1=O
Product: Cn1nc(Cl)cc(Nc2ccncn2)c1=O
Yield: 69 %

Procedure:
Using the same general procedure as described for the preparation of 101m, reaction of 2-aminopyrimidine (450 mg, 4.74 mmol) with 103a (1.06 g, 4.74 mmol) afforded 103b in 69% yield (745 mg) as an amorphous yellow solid: mp 233-235° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.92 (d, J=1.0 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H), 8.45 (s, 1H), 7.58 (dd, J=6.0, 1.0 Hz, 1H), 3.70 (s, 3H); MS (ESI+) m/z 238.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>[Cu]Br>[CH3:22][O:21][C:19](=[O:20])[CH:18]([C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:17]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: COC(=O)CC(=O)OC
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 70 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (75 g, 372 mmol) in dimethyl malonate (900 mL) was perfused with nitrogen for 15 min. Sodium methoxide (48.3 g, 894 mmol) was added in one portion and the contents exothermed to 48° C. Fifteen minutes later, copper (I) bromide (5.4 g, 37 mmol) was added in one portion and the contents were heated to 70° C. for 24 hrs. The reaction, which was 70% complete as determined by NMR, was subsequently heated to 85° C. for 5 hrs to completely consume the remaining 2-chloro4-nitrobenzoic acid. Water (900 mL) was added to the cooled reaction followed by hexanes (900 mL). The aqueous layer was separated, toluene (900 mL) was added, the mixture was filtered and aqueous layer separated. Fresh toluene (1800 mL) was added to the aqueous layer and the biphasic mixture acidified with 6N aqueous HCl (90 mL). A white precipitate formed and the contents were stirred for 18 hrs. The product was filtered off and dried to give a white solid (78.1 g, 70%) mp 153° C.
Reaction SMILES: [CH3:1][NH2:2].O.Br[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C1COCC1>[CH3:1][NH:2][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a stirred solution of 40 wt % methylamine in H2O (50 mL, 581 mmole) in THF (50 mL) at 0° C. was added 2-(bromomethyl)naphthalene (10 g, 43 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 16 hr, then was then concentrated under vacuum. The residue was taken up in Et2O and washed with 1.0 N NaOH then with brine, dried (Na2SO4), and concentrated to dryness. Purification by flash chromatography on silica gel (98:2 to 9:1 CHCl3/methanol containing 5% NH4OH) gave the tide compound (3.95 g, 54%) as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.85 (m, 3 H), 7.79 (s, 1 H), 7.49 (m, 3 H), 3.94 (s, 2 H), 2.53 (s, 3 H).