Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(C(C(C(OCC)=O)O)O)(OCC)=[O:26].C(N(C(C)C)CC)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH2:14][S@:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:26])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S([O-])([O-])=S
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)c1ccccc1
Product: Cc1c(OCC(F)(F)F)ccnc1C[S@@](=O)c1nc2ccccc2[nH]1
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]thio]benzimidazole (100 g), toluene (500 mL), water (0.23 mL) and diethyl (+)-tartrate (10.6 mL) were mixed. Under a nitrogen atmosphere, titanium (IV) isopropoxide (8.3 mL) was added to the mixture at 50° C. to 60° C., and the mixture was stirred at the same temperature for 30 min. Under a nitrogen atmosphere, diisopropylethylamine (16.3 mL) was added to the obtained mixture at 0° C. to 10° C., cumene hydroperoxide (156.8 mL, content 82%) was added at −10° C. to 10° C., and the mixture was stirred at −10° C. to 10° C. for 4 hr to give a reaction mixture. 25% Aqueous sodium thiosulfate solution (135 g) was added to ½ of the reaction mixture under a nitrogen atmosphere to decompose remaining cumene hydroperoxide. The mixture was concentrated to 230 mL, diisopropyl ether (900 mL) was added to the obtained concentrate at room temperature, and the mixture was stirred at the same temperature to allow crystal precipitation. The crystals were separated and washed successively with diisopropyl ether/n-heptane (1/1) (100 mL) and municipal water (100 mL×2) (pale-yellowish white crystals, 101.6 g). The total amount of the wet crystal was dissolved in acetone (200 mL), and the mixture was stirred for 13 min. To a mixture of acetone (75 mL) and municipal water (375 mL) was added dropwise the acetone solution over 17 min, and municipal water (525 mL) was added dropwise over 15 min. After cooling to 10° C. or below, the mixture was stirred for about 2 hr. The crystals were collected by filtration, washed with cooled acetone/municipal water (1/5, 100 mL), and then with municipal water (100 mL) to give pale-yellowish white crystals (103.2 g) of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]benzimidazole 1.5 hydrate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:18])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: C[Mg]Br
Reactant: COc1cc(C(=O)c2ccccc2)ccc1Br
Solvent: C1CCOC1
Product: COc1cc(C(C)(O)c2ccccc2)ccc1Br
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-methoxyphenyl)-phenylmethanone (200 mg, 0.687 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29]>>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29].[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][CH2:24][N:18]([CH3:17])[CH2:19][CH2:20]1)[CH2:11][CH3:12]
Reactant: CN1CCCNCC1
Reactant: CCCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: CCCOCCn1c(N2CCCN(C)CC2)nc2ccccc21
Yield: 59.3 %

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(n-propoxy)ethyl]benzimidazole (2.83 g), N-methylhomopiperazine (3.00 g) and fumaric acid (2.04 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(n-propoxy)ethyl]-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (2.86 g) as colorless needles, m.p. 159.5°-160.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=1)[C:9](O)=[O:10])=[O:5])[CH3:2].O=S(Cl)Cl.CN.C[CH2:27][N:28](CC)CC>CCN(CC)CC>[CH3:27][NH:28][C:9]([C:8]1[CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:14]=[C:6]([CH:7]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:10]
Reactant: CCOC(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)NC)cc(C(=O)OCC)c1
Temperature: 95 °C
Yield: 66.7 %

Procedure:
1 drop of Et3N (catalytic) was added to a stirred solution of 3,5-bis(ethoxycarbonyl)benzoic acid (0.42 g, 1.5 mmol, 1 eq) in SOCl2 (4 mL, 6.54 g, 55 mmol, 37 eq) under Ar. The solution was heated to reflux at 95° C. After 2 h the reaction was cooled to room temperature, and the solvent was removed in vacuo. The resulting yellow oil was placed under Ar and dissolved in 5 mL anh. CH2Cl2. The solution was cooled to 0° C., and MeNH2 (2.0 M in THF, 2.7 mL, 5.4 mmol, 3.6 eq) was added with stirring. After stirring for 1 h, Et3N (0.2 mL, 0.15 g, 1.5 mmol, 1 eq) was added. The reaction was stirred at 0° C. to room temperature overnight. The solvent was removed in vacuo. The residue was diluted with saturated NaHCO3/water and extracted with EtOAc (×3). The combined organics were washed with water (×2), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.2914 g (1.0 mmol, 70% yield) of diethyl 5-(methylcarbamoyl)isophthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([N:8]=[C:9]=[O:10])([CH3:7])[CH3:6].[C-]#N.[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5]([NH:8][C:9](=[O:10])[N:18]([CH3:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(N=C=O)c1ccc(Cl)c(Cl)c1
Reactant: CNc1ccccc1
Agent: [C-]#N
Solvent: c1ccccc1
Product: CN(C(=O)NC(C)(C)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reaction time: 8 h
Yield: 86 %

Procedure:
4.6 g of 3,4-dichloro-α,α-dimethylbenzyl isocyanate, prepared from the corresponding cyanide in the same way as in Synthesis Example 1, was added to a solution of 2.2 g of N-methylaniline in 20 ml of benzene and the mixture was heated under reflux for 2 hours. After allowing the mixture to stand overnight, the reaction solution was washed with a 2N aqueous hydrochloric acid solution, a 2N aqueous sodium hydroxide solution and water in that order, and the organic layer was dried over sodium sulfate. The layer was concentrated by evaporating off the solvent to obtain crystals, which were recrystallized from n-hexane to obtain 5.8 g of the title compound as crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][CH3:15])=[N:4][N:3]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[CH2:19][CH2:18]1>>[CH2:14]([C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)[CH2:21][CH2:22]2)=[N:3][N:4]=1)[CH3:15]
Reactant: CCc1nnc(Cl)c2cc(OC)ccc12
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Product: CCc1nnc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-ethyl-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][CH2:21][CH:22]=[O:23])(=[O:19])=[O:18])=[CH:13][CH:12]=1.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.O>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][CH2:21][CH:22]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[OH:23])(=[O:18])=[O:19])=[CH:15][CH:16]=1
Reactant: COc1ccc(S(=O)(=O)CCC=O)cc1
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CCC(O)c2ccccc2)cc1
Reaction time: 1.5 h

Procedure:
Part B: To 11.4 mL (3.2 g, 23 mM) of a 2.0 M phenylmagnesium chloride solution in THF at zero° C., was added 2.6 g (11 mmol) of 3-[(4-methoxyphenyl)sulfonyl]propan-1-al from Part A in 20 mL of THF. After 1.5 hours, the reaction mixture was cooled to zero° C. and 20 mL of saturated ammonium chloride solution was added, followed by ethyl acetate and water, the organic layer was separated and washed with 5% potassium hydrogen sulfate solution, saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 2.7 grams of crude product. This was chromatographed on silica gel using 35%-40% ethyl acetate/hexane to yield 1.7 g of pure 3-[(4-methoxyphenyl)sulfonyl]-1-phenylpropan-1-ol, m/z=324 (M+NH4).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19](=[O:26])(=[O:25])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[C:29](Cl)([Cl:31])=[O:30]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19](=[O:25])(=[O:26])[NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[C:29]([Cl:31])=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: O=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Reaction time: 0.75 h
Yield: 57.6 %

Procedure:
A solution of 1.8 g (4.81 mmole) of N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]amine (from Step E) in 35 mL of toluene was cooled to -5° C. and treated with 9.6 mL (24 mmole) of 2.5M sodium hydroxide (aqueous), followed by 7.5 mL (14.5 mmole) of phosgene in toluene. The cold mixture was stirred for 45 minutes and then filtered to remove a white precipitate. The layers of the filtrate were separated, and the toluene phase was concentrated in vacuo to yield 1.21 g (58%) of the title compound as a white solid, mp 128°-129° C.; homogeneous by TLC (3:1 hexane-EtOAc); IR spectrum νCO 1745 cm-1 ; FAB-MS m/e 438 (M+1)+. The 1H NMR spectrum indicated the presence of two rotameric forms.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[F:18][C:15]([F:16])([F:17])[C:14]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11]1)=[O:19]
Reactant: O=C(N1CCc2ccc([N+](=O)[O-])cc2C1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Yield: 83.8 %

Procedure:
7-Nitro-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline (15 g, 54.7 mmol) was stirred vigorously in EtOAc (50 mL) with 5% Pd/C (1.5 g) under hydrogen gas (1 atmosphere) for 15 h and then filtered through celite. The filtrate was concentrated under vacuum and yielded 11.2 g (84%) of the tan solid 2-(trifluoroacetyl)-1,2,3,4-tetrahydro-7-isoquinolinamine. 1H NMR (400 MHz, DMSO-d6) δ 6.84-6.79 (m, 1H), 6.46-6.40 (m, 1H), 6.35 (m, 1H), 4.95 (s, 2H), 4.56 (s, 2H), 3.76-3.68 (m, 2H), 2.74-2.66 (m, 2H).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)([CH3:3])[CH3:2].Cl[C:11]1[CH:16]=[C:15]([S:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[S:17][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)[CH:16]=1
Reactant: CC(C)c1csc(N)n1
Reactant: Clc1cc(Sc2c(Cl)cccc2Cl)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)c1csc(Nc2cc(Sc3c(Cl)cccc3Cl)ccn2)n1
Yield: 38.1 %

Procedure:
Using the method of Example 3, Step B, 4-isopropylthiazol-2-amine (0.245 g, 1.72 mmol), 2-chloro-4-(2,6-dichlorophenylthio)pyridine (0.500 g, 1.72 mmol), potassium phosphate (0.402 g, 1.89 mmol), Pd2(dba)3 (0.079 g, 0.086 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.050 g, 0.086 mmol) were reacted to provide N-(4-(2,6-dichlorophenylthio)pyridin-2-yl)-4-isopropylthiazol-2-amine (0.260 g, 38% yield) as a white powder. 1H NMR (d6-DMSO) δ 11.07 (s, 1H), 8.10 (d, 1H), 7.76 (d, 2H), 7.64 (t, 1H), 6.57 (s, 1H), 6.56 (d, 1H), 6.51 (s, 1H), 2.82 (hextet, 1H), 1.18 (d, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1nc2cnccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2cnccc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 6.2 %

Procedure:
A mixture of 1-(1-phenyl-1H-imidazo[4,5-c]pyridin-2-yl)ethylamine (184 mg, 0.77 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (256 mg, 1.08 mmol) and DIPEA (0.25 mL, 1.39 mmol) in 1-butanol (2 mL) was stirred at 90° C. in a sealed microwave tube for 16 h. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM), then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 60 min gradient 20-98% 0.1% HCO2H in acetonitrile/water) to give 236 as a white solid (0.017 g, 6%). LCMS (method K): Rt 2.04 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 12.89 (1H, s), 8.94 (1H, s), 8.30 (1H, d, J=5.54 Hz), 8.09-8.00 (2H, m), 7.65-7.50 (5H, m), 7.12 (1H, d, J=5.57 Hz), 5.53 (1H, s), 1.58 (4H, d, J=7.36 Hz)
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:50][CH2:49][CH2:48][CH2:47][N:46]([CH3:51])[CH3:45])=[O:27])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.019 g (0.19 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-70:30) gave 0.045 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-279) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[OH:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O>Cl[Cu].C(#N)CCC>[CH3:13][C:12]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:8]([OH:20])[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:11]=1[C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:20])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]=1[CH3:13]
Reactant: Cc1ccc(-c2ccccc2)c(O)c1-c1ccccc1
Agent: Cl[Cu]
Agent: O=O
Solvent: CCCC#N
Product: Cc1c(-c2cc(-c3ccccc3)c(O)c(-c3ccccc3)c2C)cc(-c2ccccc2)c(O)c1-c1ccccc1
Temperature: 100 °C

Procedure:
To a 250 mL three necked round bottom flask, equipped with a condenser and magnetic stirrer was added 100 g (0.48 mol) of diphenylacetone and 33.3 g (0.48 mol) of acrolein, 50 mL of diethylamine and 10 mL of triethylamine. After reacting for 3 hours at room temperature methanol was added to the reaction mixture and the product crystallized to yield 101 g (85%) of 3-methyl-2,6-diphenyl-2-cyclohexanone, m.p.: 99°-101° C. Dehydrogenation of 80 g (0.32 mol) of this product in the presence of 4 g of 5% palladium on carbon catalyst was carried out for 20 min at 260° C. The reaction mixture was cooled and dissolved in hot ethanol and filtered to yield 65.1 g (83%) of 2,6-diphenyl-3-methylphenol. 50 g of 2,6-diphenyl-3-methylphenol was treated with 3.8 g of CuCl and 400 mL of butyronitrile. The reaction was heated to 100° C. while passing oxygen through for 4 hours. A while solid precipitated during the reaction.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]1>CCO>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Fc1ccccn1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccn2)C1
Temperature: 120 °C
Yield: 19 %

Procedure:
A mixture of 2-fluoropyridine (58.3 mg, 0.600 mmol), tert-butyl pyrrolidin-3-ylcarbamate (55.9 mg, 0.300 mmol), and TEA (84.0 μL, 0.600 mmol) in EtOH (1 mL) was heated at 120° C. for 30 min. The reaction was concentrated and the crude was purified by flash chromatography (12 g silica gel) using hexanes/EtOAc (0-50% over 10 min, flow rate 30 mL/min) to give Intermediate 48A (15 mg, 0.057 mmol, 19% yield) as a white solid. LCMS=264.3 [M+1], RT=1.11 min (Method H). 1H NMR (400 MHz, chloroform-d) δ ppm 8.15 (1H, dd, J=5.05, 1.01 Hz), 7.44 (1H, ddd, J=8.59, 6.95, 1.89 Hz), 6.55 (1H, dd, J=6.44, 5.18 Hz), 6.35 (1H, d, J=8.34 Hz), 4.74 (1H, br. s.), 4.35 (1H, br. s.), 3.71 (1H, dd, J=10.61, 6.06 Hz), 3.46-3.64 (2H, m), 3.34 (1H, dd, J=10.61, 4.04 Hz), 2.27 (1H, td, J=13.20, 7.45 Hz), 1.96 (1H, td, J=12.51, 5.56 Hz), 1.45 (9H, s).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8](CO)[CH2:9][N:10]1[C:19]([C:20]#[N:21])=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:29][CH3:30])[CH:16]=2)[C:11]1=[O:31]>O.C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:29][CH3:30])[CH:16]=3)[C:11](=[O:31])[N:10]([CH2:9][CH:8]=[O:7])[C:19]=2[C:20]#[N:21])[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(=O)n(CC(O)CO)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(=O)n(CC=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 8 h

Procedure:
A solution of sodium periodate (368 mg, 1.72 mmol) in water (7 mL) was added to a solution of diol 106 (0.96 mmol) in THF (15 mL) at 0° C. After 7 h an additional 1.8 equivalents of NaIO4 were added. The reaction mixture was stirred overnight then partitioned between EtOAc and NaHCO3. The aqueous phase was extracted with EtOAc and the combined extracts dried (MgSO4). Concentration gave the desired product 107.
Reaction SMILES: [Br-:1].[K+].Br([O-])(=O)=O.[K+].S(=O)(=O)(O)O.[OH-].[K+].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O.C(O)C>[Br:1][C:19]1[C:20]2=[C:20]3[C:19](=[CH:17][CH:16]=[CH:15]2)[CH:18]=[CH:17][CH:16]=[C:15]3[CH:18]=1
Reactant: [Br-]
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [O-][Br+2]([O-])[O-]
Solvent: CCO
Solvent: O
Product: BrC1=Cc2cccc3cccc1c23

Procedure:
A mixture of 1 mol of 1,2,3,5-tetrabromoacenaphthlene (C12H6Br4) in 500 g of benzene and 2 mols of potassium bromide and 0.2 mols of potassium bromate in 600 g of water was placed in a three-necked flask and stirred vigorously in a dark place. Two mols of concentrated sulfuric acid diluted with an equal volume of water was added dropwise to the mixture under agitation at about 10° C. Following a 3-hr reaction, the benzene layer was washed sequentially with water, aqueous caustic soda (2%) and water, and dried with silica gel. A solution of the dried benzene was transferred to a three-necked flask where it was dehydrobromated with a solution of about 2 mols of potassium hydroxide in hot ethanol that was added dropwise through the dropping funnel. After the reaction, the benzene layer was washed with water and dried. After distilling benzene off under vacuum, the residue was washed thoroughly with hot acetone and dried to provide a bromoacenaphthylene condensate. It was estimated by elemental analysis that the condensate had a rational formula of (C12H3.7 Br2.9)1. GPC showed that it had a degree of condensation l in the range of from 2 to 5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[C:25](=[NH:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]1([C:25](=[N:38][C:2]2[CH:7]=[CH:6][C:5]3[C:8]4([CH2:23][O:24][C:4]=3[CH:3]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]4=[O:22])[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc(N=C(c4ccccc4)c4ccccc4)ccc32)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.10 g, 0.26 mmol) in anhydrous toluene (5.00 mL) was added benzophenone imine (0.09 g, 0.52 mmol), sodium t-butoxide (0.03 g, 0.36 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.01 g, 0.07 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.12 g, 0.19 mmol). The reaction mixture was refluxed for 16 h, cooled down to ambient temperature, diluted with dichloromethane (50.0 mL) and filtered through a celite bed. The filtrate was concentrated in vacuo to dryness to give the title compound which was used in next step without purification.