Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[N:3]=1.[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.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:17][C:18]1[C:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:3]=2)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1
Reactant: Fc1cccc(COc2cccc(Br)n2)c1
Reactant: OB(O)c1cc(F)ncc1Cl
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: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
A mixture of 2-bromo-6-(3-fluorobenzyloxy)pyridine (145 mg, 0.514 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (144 mg, 0.822 mmol), PalladiumTetrakis (71.3 mg, 0.062 mmol), DME (3 ml), and t 2M sodium carbonate (1.028 ml, 2.056 mmol) was reaction mixture was stirred at 100° C. for 3 hr, followed by LCMS. The reaction mixture was cooled, diluted with 10 ml of ethyl acetate, filtered and concentrated to yield a crude product, which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were concentrated to constant mass, giving 100 mg of titled compound as a free base. LCMS (m/z): 333.1 (MH+), retention time=1.26 min.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=3)[C:19]2=[O:34])=[CH:13][CH:12]=1)[CH3:6]>C(O)C.O.[Fe]>[CH2:5]([O:7][C:8](=[O:35])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][N:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[C:19]2=[O:34])=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)CCc1ccc(Cn2cc(Cl)cc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccc(Cn2cc(Cl)cc(-c3ccc(N)cc3)c2=O)cc1
Temperature: 25 °C

Procedure:
Acetic acid (1 mL) followed by iron (160 mg, 2.9 mmol) were added to a solution of 3-(4-[5-chloro-3-(4-nitrophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}-propionic acid ethyl ester (0.31 g, 0.72 mmol) in ethanol (10 mL) and water (5 mL) with stirring. The mixture was then heated at reflux for 2 hours and allowed to cool to room temperature. After basification with aqueous ammonia the mixture was filtered through a pad of celite (Diatomaceous Earth) and the filtrate evaporated to dryness. The residue was taken up in aqueous sodium bicarbonate/ethyl acetate and the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. After purification by chromatography on silica gel with a gradient of 30-50% ethyl acetate in hexane the title compound was obtained as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH:26]4[CH2:28][O:27]4)[CH2:21][CH2:20]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:30][NH2:31]>>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]([OH:29])[CH2:18][N:19]3[CH2:20][CH2:21][N:22]([CH2:25][CH:26]([OH:27])[CH2:28][NH:31][CH3:30])[CH2:23][CH2:24]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: CN
Reactant: OC(CN1CCN(CC2CO2)CC1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Product: CNCC(O)CN1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Yield: 90 %

Procedure:
To (±)-1-(3,6-dibromo-carbazol-9-yl)-3-(4-oxiranylmethyl-piperazin-1-yl)-propan-2-ol (0.110 g, 0.21 mmol) is added methyl amine (3 mL, 2M in MeOH). The resulting mixture was stirred for 16 hr at it Concentration in vacuo, flash chromatography on a 2×14 cm2 column of SiO2 using (ACN:(aqueous NH4OH-25%)) (5:1) as eluting solvent gives the title compound as a white foam in a 90% yield. M.p.: 65-75° C. Slow addition of HCl (1 mL, 1M in Et2O) into a solution of the above compound in DCM (2 mL) gives the hydrochloride salt of the title compound (0.39 g) as a white solid in a 35% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:20]=[O:21]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:20]=[O:21])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCc1cn2ccnc(Cl)c2n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nc2c(Cl)nccn2c1C=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
8-Chloro-2-ethylimidazo[1,2-a]pyrazine (600 mg, 3.3 mmol) was dissolved in N,N-dimethylformamide (3.3 mL), phosphorus oxychloride (1.2 mL, 13.2 mmol) was added dropwise at room temperature, and the mixture was heated under stirring at 90° C. for 2 hours. After being allowed to cool, the reaction mixture was poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (472 mg) as white crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][N:23]=[C:24]=S)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:24]([NH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:2][C:3]=2[CH:7]=1
Reactant: S=C=NCCCCc1ccccc1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: O=S1(=O)N=C(NCCCCc2ccccc2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 4-phenylbutyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 201°-205° C.; 1H-NMR (DMSO-d6): δ 1.55 (m, 4H), 2.6 (t, 2H), 3.2 (q, 2H), 7.04 (s, 1H), 7.1-7.4 (m, 6H), 10.94 (br. s, 1H).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C@@H:10]1[NH:19][C:20]([C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([Cl:31])=[CH:26][CH:25]=2)=[O:21])=O)(C)(C)C.Cl.[CH3:33][N:34]1[CH2:39][CH2:38][C:37]2[N:40]=[C:41](C([O-])=O)[S:42][C:36]=2[CH2:35]1.[Li+]>C(O)C>[Cl:31][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:20]([NH:19][C@H:10]1[CH2:11][C@@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14][C@H:9]1[NH:8][C:6]([C:41]1[S:42][C:36]3[CH2:35][N:34]([CH3:33])[CH2:39][CH2:38][C:37]=3[N:40]=1)=[O:5])=[O:21])=[CH:30]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1

Procedure:
(1R*,2S*,4S*)-N1-tert-Butoxycarbonyl-N2-[(5-chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:14][C:15]1[C:16](F)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:14][C:15]1[C:16]([O:13][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=2)=[CH:17][C:18]([F:28])=[C:19]([CH:27]=1)[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: Oc1ccc(OC(F)(F)F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
3-chloro-4-(trifluoromethoxy)phenol (22.6 g, 0.106 mol) and tert-butyl 5-chloro-2,4-difluorobenzoate (Preparation 51, 26.4 g, 0.106 mol) were dissolved in dimethlysulfoxide (105 mL). Then potassium carbonate (29.4 g, 0.213 mol) was added portionwise to the mixture, which was stirred at room temperature for 18 hours. The reaction mixture was dropped into iced water (500 mL) and stirred vigorously for 4 hours. The resulting solid was collected by filtration then taken up in isopropanol (75 mL) and water (15 mL). The reaction was heated to 55° C., then cooled down to room temperature. The resulting solid was collected by filtration to yield the title compound as an off-white white solid (35.3 g, 75%).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH2:10]([NH:17][CH:18]1[CH2:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:20]=2[CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([N:17]([CH2:3][CH:2]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[OH:1])[CH:18]1[CH2:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][C:27]([O:29][CH3:30])=[CH:28][C:20]=2[CH2:19]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc2c(c1)CC(NCc1ccccc1)CCC2
Reactant: c1cncc(C2CO2)c1
Solvent: CCO
Product: COc1ccc2c(c1)CC(N(Cc1ccccc1)CC(O)c1cccnc1)CCC2
Yield: 11 %

Procedure:
Under nitrogen, a solution of 3-oxiranylpyridine (1.9 g) and N-benzyl-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (3.3 g) in ethanol (15 ml) was refluxed for 5 hours. After removal of ethanol in vacuo, the residue was dissolved into a mixture of aqueous sodium hydrogencarbonate and ethyl acetate. After separation, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(pyridin-3-yl)ethanol (520 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1.C(N(CC)CC)C>O.CCOCC>[Cl:8][C:7]1[C:2]([NH:11][CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH2:13]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: COc1ccc2c(c1)CCC(N)C2
Reactant: CCc1ncnc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: CCc1ncnc(NC2CCc3cc(OC)ccc3C2)c1Cl

Procedure:
1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.5 g (8.5 mmol) of 2-amino-6-methoxytetralin and 2 ml of triethylamine were heated for 10 hours at 85° C. The mixture was subsequently diluted with water and ether, the phases were separated, and the organic phase was washed with water and saturated NaCl solution. After the mixture had been dried and concentrated, the residue was purified by column chromatography with petroleum ether/ethyl acetate (8:1). This gave 2.4 g (89% of theory) of colorless crystals (melting point 70-71° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH:11]([O:14][Si](C(C)(C)C)(C)C)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl>[NH2:7][C:8]1([CH2:22][CH2:23][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1
Reactant: COCCCC1(NC(=O)OC(C)(C)C)CCC(O[Si](C)(C)C(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC1(N)CCC(O)CC1
Temperature: 25 °C

Procedure:
200 mg of the crude [4-(tert-butyl-dimethyl-silanyloxy)-1-(3-methoxy-propyl)-cyclohexyl]-carbamic acid tert-butyl ester (33, step a) were dissolved in 10 mL of dichloromethane and treated with 370 μL of trifluoroacetic acid. After stirring at room temperature until complete conversion was achieved, 2M aqueous hydrochloric acid was added, the mixture stirred for further 60 min and the aqueous phase evaporated. The crude aminoalcohol was lyophilized from water and used crude as hydrochloride in the next reaction. Rt=0.18 min, 0.37 min (Method C). Detected mass: 188.3 (M+H+).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CC([O-])(C)C.[K+].Br[C:17]1[CH:22]=[CH:21]C=C[N:18]=1>C1COCC1.O>[N:18]1[CH:17]=[CH:22][CH:21]=[CH:9][C:2]=1[O:3][CH2:4][CH:5]([OH:6])[CH2:7][OH:8]
Reactant: Brc1ccccn1
Reactant: CC1(C)OCC(CO)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCC(O)COc1ccccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
Following a literature procedure2, a solution of solketal (1.25 mL, 0.01 mol) in THF (20 mL) was stirred and cooled to 0° C. under N2 and KOtBu (1.349 g, 0.012 mol) was added. The mixture was stirred 15 min, 2-bromopyridine (1.1 mL, 0.011 mol) was added, and the mixture was stirred 18 h at room temperature, diluted with H2O, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), filtered, and evaporated to give the crude title product (288.1 mg, 17%).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH3:5][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:7][CH:8]=[O:9]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([S:3][C:6]([CH3:5])([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH:8]=[O:9])(=[O:4])[CH3:2]
Reactant: CCCCCC(C)=CC=O
Reactant: CC(O)=S
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCCCCC(C)(CC=O)SC(C)=O
Yield: 41.3 %

Procedure:
Freshly distilled thioacetic acid (64 g) was added with stirring and occasional cooling to a mixture of 98 g 3-methyloct-2-enal and 25 mg of benzoyl peroxide. After 5 hours of reflux the mixture was distilled in vacuo through a 20 cm vigreux column yielding 62.5 g (41.3%) of 3-acetylthio-3-methyloctanal, b.p. 100°-112°C/0.5 mm.
Reaction SMILES: [Br:1][C:2]1[C:25]([Br:26])=[CH:24][C:5]2[N:6]([CH2:22][CH3:23])[C:7]([N:9]3[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[C:27]#[N:28].[ClH:29].C(OCC)C>O1CCOCC1>[ClH:29].[Br:1][C:2]1[C:25]([Br:26])=[CH:24][C:5]2[N:6]([CH2:22][CH3:23])[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[C:3]=1[C:27]#[N:28]
Reactant: CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c(C#N)c(Br)c(Br)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCn1c(N2CCNCC2)nc2c(C#N)c(Br)c(Br)cc21
Temperature: 25 °C

Procedure:
tert-butyl 4-(5,6-dibromo-4-cyano-1-ethyl-1H-1,3-benzodiazol-2-yl)piperazine-1-carboxylate (Method 8A) (900 mg, 2.18 mmol) was dissolved in 1,4-dioxane (5.0 ml) and 4M HCl in dioxane (2.0 ml) was added. The mixture was stirred at room temperature until the reaction was complete (18 hrs) by LC/MS. Diethyl ether (10.0 ml) was added, product was filtered off, washed with diethyl ether and dried to afford 5,6-dibromo-1-ethyl-2-(piperazin-1-yl)-1H-1,3-benzodiazole-4-carbonitrile hydrochloride (820 mg, 1.8 mmol) 1H NMR (600 MHz, DMSO) δ 9.47 (s, 2H), 8.24 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.67-3.62 (m, 4H), 3.29 (s, 4H), 1.32 (t, J=7.2 Hz, 3H), m/z 413.9; rt 2.2.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1.[OH-].[Na+].C1(C)C=CC=CC=1>C(#N)C.O>[Cl:3][CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: ClCc1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 134 %

Procedure:
To a mechanically-stirred solution of 78.12 g of thionyl chloride in 450 mL of acetonitrile at 15° C. was added a solution of 160.75 g of 3-hydroxymethyl-6-bromopyridine in 446 mL of acetonitrile over 30 minutes. The temperature rose to 22° C. during the addition, and the reaction mixture was stirred for 15 minutes at room temperature. The mixture was cooled in an ice bath, and a solution of 70 g of NaOH in 1.4 L of water was added at such a rate that the temperature did not exceed 15° C. 603 mL of toluene was added to the mixture and stirred rapidly. The layers were separated. The aqueous phase was reextracted with toluene. The combined organic phase was concentrated in vacuo to give 181.61 g of 3-chloromethyl-6-bromopyridine.
Reaction SMILES: [OH:1][C@@:2]1([CH3:19])[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8]C(=O)OCC1C=CC=CC=1.[BrH:20]>CC(O)=O>[BrH:20].[NH2:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@:2]1([CH3:19])[OH:1]
Reactant: C[C@]1(O)CCCC[C@@H]1NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: C[C@]1(O)CCCC[C@@H]1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (±)-Benzyl (1S,2S)-2-hydroxy-2-methylcyclohexylcarbamate (81.4 mg, 0.309 mmol) was added HBr in AcOH, 33% (1 mL, 6.1 mmol) and the resulting mixture was stirred at rt under N2 for 2 h. The solvents were removed and the crude residue concentrated with EtOH (2×) and dried on high vacuum overnight to afford an orange low-melting solid which was used directly in the next step.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:43])[NH:12][CH:13]([C:17]([N:19]1[CH2:23][CH2:22][CH:21]2[N:24]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[CH2:25][CH:26]([C:27]3[C:35]4[C:30](=[CH:31][C:32]([F:36])=[CH:33][CH:34]=4)[NH:29][CH:28]=3)[CH:20]12)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:36][C:32]1[CH:31]=[C:30]2[C:35]([C:27]([CH:26]3[CH:20]4[N:19]([C:17]([CH:13]([NH:12][C:11](=[O:43])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:14]([CH3:15])[CH3:16])=[O:18])[CH2:23][CH2:22][CH:21]4[N:24]([C:37]4[N:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH2:25]3)=[CH:28][NH:29]2)=[CH:34][CH:33]=1
Reactant: CC(C)C(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1)C(C)C
Reaction time: 2 h

Procedure:
To a solution containing 74 (202 mg, 0.33 mmol) in DCM (10 mL) was added TFA (4 mL) at 0° C. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by RP-HPLC (2″ Dynamax C18, 10-70% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 125 mg (61%, 3 steps) of 75. 1H NMR (CDCl3, 300 MHz): δ8.37 (dd, J=6.0, 10.5 Hz, 2H), 8.19 (s, 1H), 8.11 (dd, J=5.4, 8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 6.99-6.88 (m, 2H), 6.74-6.68 (m 1H), 6.62-6.58 (m, 1H), 4.74-4.60 (m, 1H), 4.48-4.44 (m, 1H) 4.16-4.04 (m, 2H), 3.69 (dd, J=6.0, 11.4 Hz, 1H), 3.51-3.42 (m, 1H), 3.26 (dd, J=6.6, 13.5 Hz, 1H), 2.76 (br s, 4H), 2.53-2.47 (m, 1H), 2.44-2.39 (m, 3H), 2.21-2.01 (m, 3H), 1.39-1.32 (m, 3H), 1.06-0.96 (m, 6H) ppm. 13C NMR (CDCl3, 75 MHz) δ173.9, 170.8, 160.2 (JCF=237.4 Hz), 159.8, 136.2, 123.4, 120.9 (JCF=10.1 Hz), 116.6, 110.1, 108.5 (JCF=24.5 Hz), 97.2 (JCF=26.2 Hz), 68.2, 60.3, 59.7, 55.9, 51.4, 47.2, 38.9, 34.2, 31.5, 30.7, 19.4, 18.8, 18.0 ppm. Mass spectrum, m/z [508.3] (M)+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([NH:11][C@@H:12]2[CH2:20][C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]([CH3:22])([CH3:21])[CH2:13]2)=[N:6][C:7]([Cl:10])=[N:8][CH:9]=1)=O.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Cl:10][C:7]1[N:6]=[C:5]([NH:11][C@@H:12]2[CH2:20][C@H:19]3[N:15]([CH2:16][CH2:17][CH2:18]3)[C:14]([CH3:21])([CH3:22])[CH2:13]2)[C:4]([C:2]#[N:1])=[CH:9][N:8]=1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C(N)=O)C[C@@H]2CCCN21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a mixture of (7R,8aS)-N-(5-aminocarbonyl-2-chloropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (1.3 g) and triethylamine (1.72 mL) in THF (50 mL) was added trifluoroacetic anhydride (1.33 mL) at −78° C. After stifling for 2 h, the reaction was quenched with ice (150 mL). The aqueous solution was extracted with EtOAc (6×150 mL). The organic layers were evaporated under vacuum and the residue was purified by CombiFlash chromatography on silica gel (2N NH3 in MeOH/CH2Cl2=0-20%) to give the desired product (1.1 g, 89%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]=[N:2][N:3]=[CH:4]2)([O-:13])=[O:12]
Reactant: c1ccc2cnncc2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=[N+]([O-])c1cccc2cnncc12
Temperature: 110 °C
Yield: 47 %

Procedure:
The 5-nitrophthalazine of formula (Y) was prepared according to prior art literature (Patrick, J.; Ragunathan, R., J. Chem. Soc. Perkin Trans. I, 1993, 211). A reaction vessel charged with phthalazine (the compound of formula (X), 4.0 g, 30 mmol) in conc. 96% sulfuric acid (30 mL) was further charged with potassium nitrate (14.6 g, 144 mmol) in small portions. Once the addition was complete, the solution was heated to 110° C. overnight. The mixture was then poured over ice and neutralized with sodium hydroxide solution resulting in the formation of a precipitate. The solid was isolated by filtration to yield 2.5 g (47%) of 5-nitrophthalazine of formula (Y) which was used in the following reaction without further purification.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25])[C:15]=3[OH:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:29][C:30]1[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=1[OH:38].C(N(CC)CC)C>C1COCC1>[CH:1]1[C:13]2[N:12]([C:14]3[C:15]([OH:27])=[C:16]([CH:17]=[CH:18][CH:19]=3)[CH2:20][N:21]([CH3:26])[CH2:22][CH2:23][N:24]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[C:32]([Br:37])[C:31]=3[OH:38])[CH3:25])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CNCCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O
Reactant: Oc1c(Br)cc(Br)cc1CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCN(C)Cc1cccc(-n2c3ccccc3c3ccccc32)c1O)Cc1cc(Br)cc(Br)c1O
Reaction time: 8 h
Yield: 56.9 %

Procedure:
8 (0.218 g, 0.606 mmol) and 2-bromomethyl-4,6-dibromophenol (0.209 g, 0.606 mmol) were dissolved in 20 mL of THF. Triethylamine (1.2 mL, 8.61 mmol) was added to the slightly pink solution. A white precipitate formed immediately. The reaction was allowed to stir overnight after which time the volatiles were removed and methanol added to make a slurry. The solids were filtered and dried under vacuum resulting in a white solid (0.215 g, 57% yield).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([O:6][C:7]2[C:12]([O:13]C)=[C:11]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:21])[N:8]=2)=[C:4]([CH3:25])[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:5]([O:6][C:7]2[C:12]([OH:13])=[C:11]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]([CH3:21])[N:8]=2)=[C:4]([CH3:25])[CH:3]=1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1O

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-amine in methylene chloride was added BBr3 at 0° C. and stirred for hr. The mixture was quenched with water and extracted with chloroform. The organic layer was separated, dried, and concentrated to give the title compound. 1H NMR(CDCl3) d 7.20(s,2H), 6.12(s,1H), 4.77(d,1H), 3.27(m,1H), 2.13(s,3H), 2.10(s,6H), 1.4–1.8(m, 4H), 0.97(t,6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[Br:1][C:2]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:3]=1[CH2:4][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)c(Br)c1
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1Br

Procedure:
The title compound was prepared following the general procedure 10, starting from 2-bromo-4-cyanobenzyl bromide (Carbocor) and sarcosine tert-butyl ester hydrochloride. It was obtained as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.17 (d, J=1.6 Hz, 1H), 7.88 (dd, J=8.0, 1.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 3.82 (s, 2H), 3.31 (s, 2H), 2.31 (s, 3H), 1.43 (s, 9H). LC/MS (Method B): 338.9, 340.9 (M+H)+. HPLC (Method A) Rt 3.10 min (Purity: 99.6%).