Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[O-]CC.[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[C:19](/Cl)=[N:20]/O)=[CH:15][CH:14]=1.Cl>CCO>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:4]([C:5](=[O:7])[CH3:6])=[C:1]([CH3:2])[O:3][N:20]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)CC(C)=O
Reactant: O/N=C(\Cl)c1ccc(Br)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccc(Br)cc2)noc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
Acetylacetone (1.25 mL, 12 mmol) was added to a sodium ethoxide solution 3.09 N (3.95 mL, 12 mmol) in EtOH (22 mL) at room temperature. The resulting yellow solution was cooled with a ice-bath and a cloudy solution of (E)- and/or (Z)-4-bromo-N-hydroxy-benzenecarboximidoyl chloride (2.35 g, 10 mmol) in EtOH (8 mL) was added dropwise within 10 min keeping the temperature below 5° C. The light yellow suspension was stirred at room temperature for 3 h and then acidified with 6 N HCl and then evaporated. The resulting mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine, dried over Na2SO4 and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate:=100:0 to 7:3) afforded the title compound (2.35 g, 84%) as a light yellow oil. MS m/e: 280.1/282.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[N:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[N:22][CH:21]=1>>[F:18][C:5]1[CH:4]=[C:3]([F:19])[C:2]([C:24]2[CH:25]=[N:20][CH:21]=[N:22][CH:23]=2)=[CH:7][C:6]=1[C@:8]1([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]1
Reactant: C[C@]1(c2cc(Br)c(F)cc2F)N=C(N)OCC1(F)F
Reactant: OB(O)c1cncnc1
Product: C[C@]1(c2cc(-c3cncnc3)c(F)cc2F)N=C(N)OCC1(F)F

Procedure:
In a manner analogous to that described in Example 31, the cross-coupling reaction of (R)-4-(5-bromo-2,4-difluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A6.2) and pyrimidin-5-ylboronic acid yielded the title compound as a yellow solid. MS (ISP): m/z=341.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11][CH3:12])=[O:10].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>>[CH3:18][N:19]([CH3:21])[CH:20]=[C:8]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([C:9]([O:11][CH3:12])=[O:10])[C:2]1=[O:1]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)C1CCCCCC1=O
Product: COC(=O)C1CCCCC(=CN(C)C)C1=O

Procedure:
Methyl 2-oxo-cycloheptanecarboxylate (51 mg, 0.30 mmol) was reacted with tert.-butoxy-bis-(dimethylamino)-methane using in analogous manner the procedure described in example 45a) to give crude title compound (85 mg) as a yellow oil which was used directly in the next step. MS ISP (m/e): 226.3 [(M+H)+].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH:5]([CH3:8])[CH2:4][NH:3]1.[C:9](Cl)(=[O:13])[CH2:10][CH2:11][CH3:12]>>[C:9]([N:3]1[CH2:4][CH:5]([CH3:8])[N:6]([C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH2:7][CH:2]1[CH3:1])(=[O:13])[CH2:10][CH2:11][CH3:12]
Reactant: CC1CNC(C)CN1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)N1CC(C)N(C(=O)CCC)CC1C
Yield: 446.2 %

Procedure:
The reaction of 5 g (0.044 mole) of 2,5-dimethylpiperazine with 12.15 g (0.0114 mole) of butyryl chloride is conducted as described in Example III, and the crude product obtained is an oily solid. The solid is washed with hexane, recrystallized from hexane/acetone, and dried in vacuo for 16 hours at 55° C. over phosphorus pentoxide to yield 6.47 g of 1,4-dibutryl-2,5-dimethylpiperazine: mp, 92°-94° C., as confirmed by IR and NMR spectroscopic analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1cc(Cl)nc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(Cl)nc(Cl)c1
Yield: 101.1 %

Procedure:
Oxidation of the above alcohol (1.2 g) according to the conditions of Swern (oxalyl chloride, 0.33 ml; dimethyl sulphoxide, 0.54 ml; triethylamine, 2.35 ml) gave (2,6-dichloro-4-pyridyl)methanal (1.2 g). NMR 1H: 10.02(1H,s), 7.68(2H,s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:15][CH3:16])[CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH3:14])[CH2:3]1.[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18].C(O)=O.CO>C1COCC1.C(OCC)(=O)C.C(Cl)Cl>[CH:17]([NH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:15][CH3:16])[CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH3:14])[CH2:3]1)=[O:18]
Reactant: CCOc1ccc(OC)c2c1CCC(N)C2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(OC)c2c1CCC(NC=O)C2
Reaction time: 8 h

Procedure:
As in example 6g, 2-amino-5-ethoxy-8-methoxytetralin 408 mg (1.84 mmol) in 20 ml THF, was formylated with 360 mg (2.21 mmol) carbonyl dimidazole in 10 ml THF and 102 mg (2.21 mmol) formic acid in 3 ml THF. After stirring overnight, tlc analysis (silica gel; 10:90 CH3OH:CH2Cl2) indicated a major component, Rf 0.53, and absence of starting amine, Rf 0.06. The residue obtained on removal of solvent was dissolved in ethyl acetate, washed with 3N HCl, Na2CO3 solution, brine and dried (MgSO4). Filtration and removal of solvent in vacuo left an off-white solid, 460 mg (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH2:15]([Mg]Br)[CH:16]=[CH2:17].Cl>C1COCC1.CCOCC>[OH:6][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH2:17][CH:16]=[CH2:15]
Reactant: C=CC[Mg]Br
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)c1ccc(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A stirred solution of 8.77 g (44.7 mmol) of 2,3,4-trimethoxybenzaldehyde in 100 mL of THF was cooled in an ice bath and 55 mL of 1.0 molar (55.0 mmol) allylmagnesium bromide in ether was added dropwise over 0.5 h. The cooling bath was allowed to warm up and the mixture was stirred overnight at room temperature. A 200 mL portion of 5% aqueous HCl was added and the mixture was extracted with two 200 mL portions of ether. The combined ether extracts were washed with 50 mL of saturated aqueous NaHCO3, dried over MgSO4 and the solvent removed in vacuo to leave 10.30 g of 4-hydroxy-4-(2,3,4-trimethoxyphenyl)butene as an oil. 1H NMR (CDCl3) d 2.5 (m, 2H), 3.8 (s, 6H), 3.9 (s, 3H), 4.9 (t, 1H), 5.1 (m, 2H), 5.85 (m, 1H), 6.65 (d, 1H), 7.05 (d, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([C:21](OC)=[O:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].CC(C[Al]CC(C)C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][O:19][CH3:20])=[C:8]([CH2:21][OH:22])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(C(=O)OC)c1-c1ccc(Cl)cc1OCOC
Agent: CC(C)C[Al]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCn1ncc(CO)c1-c1ccc(Cl)cc1OCOC
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of Methyl 1-n-butyl-5-(4-chloro-2-methoxymethoxyphenyl)-1H-pyrazol-4-yl carboxylate (10.00 g, 0.028 mol) in 200 mL of CH2Cl2 at 0° C. was added 85.2 mL of 1.5 M Dibal-H in toluene. After stirring for 1 h. the reaction was quenched with MeOH (100 mL) followed by addition of 35 mL of conc. HCl in 200 mL of water. The resulting mixture was stirred for 15 min. and extracted with CH2Cl2 (3×200 mL). The combined organic extracts were washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 9.50 g (97%) of the title compound as a oil: MS (ESI) m/z 325 (M+H)+ ; 1H NMR (400 MHz, CDCl3) d 7.63 (s, 1 H), 7.13-7.29 (m, 3 H), 5.09 (s, 2 H), 4.36 (dd, 2 H), 3.80-3.98 (m, 2 H), 3.35 (s, 3 H), 1.70 (m, 2 H), 1.18 (m, 2 H), 0.81 (t, 3 H).
Reaction SMILES: [NH2:1][C:2]1([CH2:18][O:19][CH2:20][CH2:21][C:22]#[N:23])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C[Al](C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[Br:17][C:5]1[CH:4]=[C:3]2[C:2]3([N:1]=[C:22]([NH2:23])[CH2:21][CH2:20][O:19][CH2:18]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1
Reactant: N#CCCOCC1(N)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: NC1=NC2(COCC1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 15.5 %

Procedure:
A 500-mL RBF was charged with 3-((5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)propanenitrile (3.967 g, 10.05 mmol) and toluene (100 mL) to give a clear solution. Trimethylaluminum (10.55 mL of a 2M solution in toluene, 21.11 mmol) was added, and the resulting mixture was stirred for 5 min. A reflux condenser was attached, and the mixture was heated to reflux for 1 h. After the mixture had cooled to RT, a saturated aq. Rochelle's salt solution (200 mL) was slowly added. The mixture was stirred vigorously for 48 h and was then diluted with EtOAc (200 mL) and water (300 mL). The layers were separated, and the aq. layer was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (200 mL), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM/MeOH and filtered to give 615 mg of the desired product an off-white solid. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (0-10% MeOH/DCM). The product obtained from chromatography was combined with the above solid to give 7-bromo-3-chloro-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a cream-colored solid. 1H NMR (400 MHz, DMSO-d6) δ=8.37 (d, J=0.4 Hz, 1 H), 7.62-7.43 (m, 2 H), 7.35 (s, 1 H), 7.22 (dd, J=0.5, 8.4 Hz, 1 H), 6.27 (br. s., 2 H), 3.94-3.72 (m, 2H), 3.70-3.47 (m, 2 H), 3.05-2.75 (m, 2 H). MS m/z=394.0. Calc'd for C16H14BrClN3O2: 394.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12].[H-].[Na+].[CH3:28]I>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:28])[C:11]([C:13]1[C:14]([F:25])=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH3:23])[C:17]=2[CH:24]=1)=[O:12]
Reactant: CI
Reactant: COc1ccc(CC(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(C)C(=O)c2cc3c(cc2F)OCC(=O)N3C)c(Cl)c1

Procedure:
In analogy to Example 1, step 2, 6-[2-(2-chloro-4-methoxy-phenyl)-acetyl]-7-fluoro-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with sodium hydride and methyl iodide to give the title compound as an off-white oil. MS (m/e, ISP neg. ion)=376.2 [M−H+].
Reaction SMILES: CC[C@H]([C@H](CN(C)C)C)C1C=CC=C(O)C=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([C:31](=[O:34])[CH2:32][CH3:33])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[CH3:36][N+:37](=[CH2:39])[CH3:38].C(Cl)(=O)C>C(#N)C>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([C:31](=[O:34])[CH:32]([CH3:33])[CH2:39][N:37]([CH3:38])[CH3:36])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=[N+](C)C
Reactant: CCC(=O)c1cccc(OCc2ccccc2)c1
Agent: CC[C@@H](c1cccc(O)c1)[C@@H](C)CN(C)C
Agent: [Cl-]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: CC(CN(C)C)C(=O)c1cccc(OCc2ccccc2)c1

Procedure:
WO2008/012046 describes another method for the preparation of tapentadol, wherein 1-(3-(benzyloxy)phenyl)propan-1-one is reacted with N-Methyl-N-methylene-methaneaminium chloride in presence of acetyl chloride and solvent acetonitrile to obtain compound 1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The compound is resolved with L-(−)-dibenzoyltartaric acid to get (S)-1-(3-(benzyloxy)phenyl)-3-(dimethylamino)-2-methylpropan-1-one. The isolated compound is then reacted with ethyl magnesium bromide undergoing Grignard reaction to isolate (2S,3R)-3-(3-(benzyloxy)phenyl)-1-(dimethylamino)-2-methylpentan-3-ol, which on reaction with trifluoroacetic anhydride in acetic acid results in acetylated compound. The acetylated compound on hydrogenolysis results in the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I.
Reaction SMILES: C(O[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.[C:24]1([CH:30]2[CH2:35][CH2:34][CH2:33][CH:32]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[NH:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.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>[C:36]1([CH:32]2[CH2:33][CH2:34][CH2:35][CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:31]2[CH2:5][CH:6]=[CH:7][CH2:8][N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)OCC=CCN(Cc1ccccc1)Cc1ccccc1
Reactant: c1ccc(C2CCCC(c3ccccc3)N2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C(=CCN1C(c2ccccc2)CCCC1c1ccccc1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-acetoxy-4-dibenzylamino-2-butene (3.0 g, 9.8 mmol) and 2,6-diphenylpiperidine (2.3 g, 9.8 mmol) in THF (25 ml) is treated with tetrakis(triphenylphosphine)palladium (0) (0.5 g, 0.45 mmol) and stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The residue is redissolved in THF (100 ml) and treated with 20% aqueous sodium hydroxide (25 ml). The mixture is stirred for one hour, concentrated, and extracted with diethyl ether. The ether extracts are dried and concentrated to give an orange oil which is purified by chromatography (silica gel; 5% ethyl acetate in hexanes) to give the title compound in a yield of 2.8 g (59%) as a clear oil. MS m/z 486 (M+)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S-:17].[K+]>C1(C)C(C)=CC=CC=1>[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[S:17][C:2]1[CH:3]=[C:4]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Fc1ccc([S-])c(F)c1
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of 3'-chloro-4'-nitroacetophenone (2.4 g), potassium 2,4-difluorothiophenoxide (2.7 g), and N,Ndimethylformamide (5 ml) in xylene (50 ml) was stirred for 8 hours at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residual solid was recrystallized from ethanol to give prisms of 3'-(2,4-difluorophenylthio)-4'-nitroacetophenone (2.3 g).
Reaction SMILES: C([Li])CCC.CC(C)([O-])C.[K+].[F:12][C:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:26])[C:17]=2[CH:16]=[CH:15][CH:14]=1.[B:27](OC)([O:30]C)[O:28]C.Cl>O1CCCC1.O>[F:12][C:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[F:26])[C:17]=2[CH:16]=[CH:15][C:14]=1[B:27]([OH:30])[OH:28]
Reactant: Fc1cccc2c1Cc1c(F)cccc1-2
Reactant: COB(OC)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 0.38 h

Procedure:
A solution of 94 mmol of n-butyllithium (1.6 M solution in hexane) in 50 ml of dry tetrahydrofuran is cooled to ≦70° C. and admixed dropwise under a protective gas atmosphere with a solution of 94 mmol of potassium tert-butoxide in 100 ml. of the same solvent. After stirring for 15-30 min, a solution of 78 mmol of 1,8-difluorofluorene in 200 ml of tetrahydrofuran is added dropwise at such a rate that the internal temperature is always below −70° C. Subsequently, stirring is continued at this temperature for another 2 h. A solution of 117 mmol of trimethyl borate in 100 ml of tetrahydrofuran is then added dropwise and the mixture is allowed to thaw gradually. The reaction mixture is admixed at −10° C. with 50 ml of water and acidified to pH I with concentrated hydrochloric acid. The phases are separated, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulfate, and the solvent is removed under reduced pressure. 1,8-Difluorofluorene-2-boronic acid is obtained which is reacted further without purification.
Reaction SMILES: Cl.[F:2][CH:3]([F:38])[C:4]1[N:9]=[CH:8][C:7]([CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[C:19](=[O:37])[NH:20][C:21]1[NH:22][C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[C:24]([CH3:26])[N:25]=1>O>[NH2:11][CH2:10][C:7]1[CH:6]=[C:5]([C:19]([NH:20][C:21]2[NH:22][C:23]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[C:24]([CH3:26])[N:25]=2)=[O:37])[C:4]([CH:3]([F:38])[F:2])=[N:9][CH:8]=1
Reactant: Cc1nc(NC(=O)c2cc(CNC(=O)OC(C)(C)C)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: O
Product: Cc1nc(NC(=O)c2cc(CN)cnc2C(F)F)[nH]c1-c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 57.2 %

Procedure:
Add hydrochloric acid (10 mL, 40.0 mmol, 4 M in 1,4 dioxane) to tert-butyl N-[[6-(difluoromethyl)-5-[[4-methyl-5-[4-(trifluoromethyl)phenyl]-1H-imidazol-2-yl]carbamoyl]-3-pyridyl]methyl]carbamate (0.212 g, 0.403 mmol) and stir overnight. Dilute with water, and extract with Et2O. Adjust the pH to ˜8 with a saturated sodium bicarbonate aqueous solution. Extract with EtOAc (3×30 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify by reverse phase flash chromatography (Analogix® 40 g @ 40 mL/min) eluting with a gradient of 2-55% ACN/water over 30 minutes. Concentrate the appropriate fractions under reduced pressure until all the ACN is removed and only water remains. Add a saturated sodium bicarbonate aqueous solution (30 mL), and extract with EtOAc (3×20 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound as a light yellow solid (0.098 g, 57% yield). 1H NMR (400.43 MHz, d6-DMSO) δ 8.71-8.69 (m, 1H), 8.16 (s, 1H), 7.79-7.77 (m, 2H), 7.69-7.67 (m, 2H), 7.42-7.28 (m, 1H), 3.81 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[C:47](=[O:48])[C:39]4[CH:40]=[C:41]5[N:46]([C:38]=4[CH:37]=[N:36]3)[CH2:45][CH2:44][CH2:43][CH2:42]5)[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[C:47](=[O:48])[C:39]3[CH:40]=[C:41]4[N:46]([C:38]=3[CH:37]=[N:36]2)[CH2:45][CH2:44][CH2:43][CH2:42]4)=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:23][O:24][CH2:25]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c(cc6n5CCCC6)c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ncc5c(cc6n5CCCC6)c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 193g (180 mg, 0.28 mmol) in methanol (20 mL) was added NaBH4 (32 mg, 0.84 mmol). The mixture was stirred at 20° C. for 2 h and quenched with water. It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 193 (140 mg, 78%) as an off-white solid. MS-ESI: [M+H]+ 650.4. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=2.0 Hz, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.47 (s, 1H), 8.48 (s, 1H), 7.85 (d, J=2.5 Hz, 1H), 7.52-7.50 (m, 2H), 7.38-7.36 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.49 (s, 1H), 4.72 (t, J=5.0 Hz, 1H), 4.57-4.54 (m, 2H), 4.47 (t, J=6.0 Hz, 1H), 4.41 (t, J=6.0 Hz, 1H), 4.33-4.29 (m, 2H), 4.28-4.25 (m, 2H), 3.71-3.65 (m, 1H), 3.60 (s, 3H), 3.41-3.77 (m, 1H), 3.10-3.08 (m, 1H), 2.98-2.90 (m, 3H), 2.57-2.52 (m, 1H), 2.35-2.30 (m, 2H), 2.18-2.16 (m, 1H), 2.06-2.0 (m, 2H), 1.89-1.82 (m, 2H), 0.93 (d, J=6.0 Hz, 3H).
Reaction SMILES: Cl.[NH:2]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH:15]([CH2:21][C:22]([OH:24])=O)[C:16](=[O:20])[NH:17]2)=[CH:12][CH:11]=1)[C:3]([NH2:5])=[NH:4].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>CN(C=O)C>[CH3:35][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][C:22](=[O:24])[CH2:21][CH:15]2[CH2:14][C:13]3[C:18](=[CH:19][C:10]([O:9][CH2:8][CH2:7][CH2:6][NH:2][C:3]([NH2:5])=[NH:4])=[CH:11][CH:12]=3)[NH:17][C:16]2=[O:20])(=[O:33])=[O:32])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: N=C(N)NCCCOc1ccc2c(c1)NC(=O)C(CC(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)CC2Cc3ccc(OCCCNC(=N)N)cc3NC2=O)cc1
Temperature: 25 °C
Reaction time: 504 h
Yield: 6.1 %

Procedure:
To [7-(3-guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid hydrochloride (0.90 g) was added para-toluenesulfonamide (0.65 g), 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.73 g), dimethylaminopyridine (0.05 g), and DMF (40 mL) and the resulting slurry formed a solution as it was stirred under N2 at room temperature for 21 days. The DMF was removed by vacuum distillation. The golden oil was triturated with CH2Cl2 (25 mL) followed by EtOAc (25 mL). The resulting oil was dissolved in 10 mL of 25% CH3CN/H2O and chromatographed on a C18 reverse phase column, eluting with a gradient of 10% CH3CN/H2O to 40% CH3CN/H2O to afford the title compound (73 mg) as an ivory solid after lyophilization.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][C:28]([CH3:34])=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:29][C:28]([CH3:34])=[CH:27][N:26]=1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1cnc(F)c(B(O)O)c1
Product: Cc1cnc(F)c(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)c1
Yield: 37 %

Procedure:
Following the procedure for Example 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6, and 2-fluoro-5-methylpyridin-3-ylboronic acid were reacted to give 402 (0.054 g, 37%). 1H NMR (400 MHz, DMSO) δ 8.74 (t, J=2.0, 1H), 8.11 (s, 1H), 8.07-7.97 (m, 2H), 7.60 (d, J=8.5, 1H), 7.21 (d, J=8.4, 1H), 5.82 (dt, J=13.2, 6.6, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 2.37 (s, 3H), 1.54 (d, J=6.6, 6H). MS (ESI(+)): m/z 422.1 (M+H)