Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])(O)[CH2:5][CH2:4]1)[CH3:2].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2cccc(SC)c2F)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CC=C(c2cccc(SC)c2F)CC1
Temperature: 70 °C
Yield: 57.6 %

Procedure:
A mixture of 1-ethyl-4-[2-fluoro-3-(methylthio)phenyl]piperidin-4-ol (42 g, 156 mmol), sulphuric acid (cone, 8.5 ml) and toluene (200 ml) was heated in a Dean-Stark trap for 20 h. The mixture was cooled to 70° C., water (200 ml) was added and the phases were separated. The aqueous phase was basified with aqueous sodium hydroxide (5 M) and extracted with ethyl acetate (2×50 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give the title compound (22.6 g). MS m/z (rel. intensity, 70 eV) 251 (M+, bp), 236 (85), 147 (65), 146 (45), 110 (44).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCCCO1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCC1CCCCO1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 2-hydroxymethyl-tetrahydropyran, there is obtained 2-tetrahydro-2H-pyranylmethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a syrup, mass spectrum m/e: M+ 336 (30), 237 (78), 194 (100), 99 (60);
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH2:6])=[S:5])[CH3:2].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(O)C>[CH2:1]([NH:3][C:4]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:6]=1)[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCNC(N)=S
Solvent: CCO
Product: CCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 42 was repeated but using 10 g of ethylthiourea, 20 g of ethyl bromopyruvate and 100 ml of ethanol, giving the title compound as a pale yellow powder.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][S:17][CH2:18][CH2:19][NH2:20].CO.C(OC(C)C)(C)C>>[CH3:16][S:17][CH2:18][CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: CSCCN
Solvent: CC(C)OC(C)C
Solvent: CO
Product: CSCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Yield: 66.7 %

Procedure:
A mixture of trans-stilbene oxide (1.18 g, 0.006 mol) and 2-(methylthio)ethylamine (0.78 g, 0.0085 mol) was heated at 140° C. in an oil bath for 15 hours. The cooled solid reaction mixture was triturated with isooctane and the red-brown solid collected. This was triturated with methanol-isopropyl ether giving an off-white solid (1.15 g, 67% yield); mp 163°-165° C.
Reaction SMILES: [CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].C[O:13][P:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]([CH2:10][CH3:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([P:14](=[O:13])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: COP(c1ccccc1)c1ccccc1
Reactant: CCCCC(C)(CC)C(=O)Cl
Product: CCCCC(C)(CC)C(=O)P(=O)(c1ccccc1)c1ccccc1

Procedure:
Using a method similar to that of Example 1, 88 parts of 2-methyl-2-ethylhexanoic acid chloride and 108 parts of methoxydiphenylphosphine give 165 parts of 2-methyl-2-ethylhexanoyl-diphenylphosphine oxide as an oily crude product. Column chromatography over silica gel (eluant: a 3:1 mixture of toluene and ether) gives the product as a pale yellowish oil. Yield 154 parts (90% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[C:10]2=[O:30])[CH:6]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]3[N:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[C:10]3=[O:30])[CH:6]=2)=[CH:35][N:34]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCn1cc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(-c2cnn(CCn3ncc4ccc(-c5ccc(OC(F)(F)F)cc5)cc4c3=O)c2)cn1
Temperature: 85 °C

Procedure:
A mixture of 2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (35 mg, 0.073 mmol), 2-methoxypyrimidin-5-ylboronic acid (13 mg, 0.087 mmol), dppf(Pd)Cl2 (2.7 mg, 0.0037 mmol), potassium carbonate (20 mg, 0.015 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) and degassed isopropanol (0.5 mL) was heated at 85° C. for 3 hours. The layers were separated, the organic layer was concentrated and the residue was purified by reverse phase HPLC to provide 2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C25H19F3N6O3. 509.2 (M+1). 1H NMR (DMSO) δ 8.74 (s, 1H), 8.38-8.44 (m, 2H), 8.26 (dd, J=2.0, 8.0 Hz, 1H), 8.20 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.84 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 4.56 (s, 4H), 3.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:5](O)=[N:6][CH:7]=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:13])=O>C(#N)C.C(OCC)(=O)C>[Cl:13][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cncnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cncnc1Cl
Temperature: 25 °C
Yield: 32.6 %

Procedure:
The mixture of 5-nitropyrimidin-4-ol (1.04 g) and phosphorus oxychloride (5.66 g) in acetonitrile (10 mL) was stirred at reflux for 2 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (50 mL), and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (50 mL) then brine (50 mL), and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:3 ethyl acetate/heptane) to afford 4-chloro-5-nitropyrimidine (383 mg, 33%) as a colorless oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25](C=O)=[CH:24][CH:23]=4)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:30][OH:31]>C(O)(=O)C>[ClH:1].[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[CH:24][C:25]([CH2:7][N:2]5[CH2:3][CH2:4][O:31][CH2:30][CH2:9]5)=[CH:26][CH:27]=4)[CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=Cc1ccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc3c2)cc1
Reactant: CO
Agent: Cl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(-c3ccc(CN4CCOCC4)cc3)cc2s1

Procedure:
N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-(4-formylphenyl)-1-benzothiophene-2-carboxamide hydrochloride (Example 23A) in 1.5 ml of a 6:1 mixture of methanol and acetic acid. 2 h at room temperature and 6 h at 80° C. are followed by purification by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 87.7 mg (88% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:31]=[N+:32]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:17]=2)=[N:10][C:9]([Br:26])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 275.9 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (2.00 gm, 4.76 mmol) was dissolved in trifluoroacetic acid (26 mL) and the yellow solution was cooled in an ice-bath. Powdered sodium nitrite (0.657 gm, 9.52 mmol) was added with stirring to give a dark red mixture. After 30 minutes, powdered sodium azide (3.09 gm, 47.6 mmol) was added followed by diethyl ether (26 mL). The light red mixture was stirred in the ice-bath for 30 minutes. The reaction was partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to about 50 mL on the rotary evaporator. The resulting solid was collected by filtration and washed three times with EtOAc to give methyl 3-azido-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)isonicotinate (5.86 gm, 72% yield). Removal of the solvent from the filtrate followed by flash silica gel chromatography (step gradient elution with methylene chloride containing 0 to 2% MeOH) afforded another 1.58 gm of product. MS (ESI) m/z 446 and 448 (M+H). 1H NMR (CDCl3) δ ppm 7.82-7.80 (3H, m), 7.49-7.53 (2H, m), 4.02 (3H, s), 3.69-3.88 (4H, m), 3.57-3.70 (2H, m), 3.40-3.53 (2H, m).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[C:7]([CH2:9][C:10]([NH2:12])=[S:11])#[N:8].C(N(CC)CC)C>CCO>[CH2:4]([C:3]1[N:12]=[C:10]([CH2:9][C:7]#[N:8])[S:11][CH:2]=1)[CH3:5]
Reactant: N#CCC(N)=S
Reactant: CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCc1csc(CC#N)n1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 1-bromo-2-butanone (10.3 g, 57.98 mmol) in EtOH (200 mL) were added 2-cyanothioacetamide (5.8 g, 57.98 mmol) and triethylamine (1.59 mL, 11.6 mmol) and the solution was stirred under reflux for 1 h. After cooling down to r.t., the solvent was removed. The orange solid obtained was washed with AcOEt then cyclohexane, and recrystallized from EtOH to afford 7.2 g of the title compound as orange needles (Y=81%).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.F[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:28]=[CH:27][C:23]4[NH:24][CH:25]=[N:26][C:22]=4[CH:21]=3)[N:16]=2)=[CH:11][C:10]=1[C:29]([F:32])([F:31])[F:30].[ClH:33].O1CCOCC1>CN(C=O)C.C(Cl)(Cl)Cl.CO.O>[ClH:33].[CH:3]1([CH2:6][O:7][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:28]=[CH:27][C:23]5[NH:24][CH:25]=[N:26][C:22]=5[CH:21]=4)[N:16]=3)=[CH:11][C:10]=2[C:29]([F:31])([F:32])[F:30])[CH2:5][CH2:4]1
Reactant: Fc1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C(F)(F)F
Reactant: OCC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(-c2nc(-c3ccc4[nH]cnc4c3)no2)ccc1OCC1CC1
Reaction time: 0.25 h

Procedure:
To a suspension of 60% NaH (68.0 mg) in DMF was added cyclopropylmethanol (99 mg) at 0° C., followed by stirring at the same temperature for 15 min, and then 5-{5-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (120 mg) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then added with water. It was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (CH3OH/chloroform=0 to 5%) to obtain an oily substance. A solution of the oily substance in chloroform-CH3OH was added with a 4M HCl/dioxane solution (0.5 ml), and concentrated to obtain 5-{5-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole hydrochloride (20 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([O:12][CH3:13])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].C([Li])CCC.[B:21](OC)([O:24]C)[O:22]C.[Cl-].[NH4+]>O1CCCC1>[CH3:15][O:14][C:3]1[CH:4]=[C:5]([CH:10]([O:12][CH3:13])[CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[B:21]([OH:24])[OH:22]
Reactant: COB(OC)OC
Reactant: COc1cc(C(C)OC)cc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(C)OC)cc(OC)c1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a tetrahydrofuran (200 ml) solution of 2-bromo-1,3-dimethoxy-5-(1-methoxyethyl)benzene (7.39 g, 26.9 mmol), was added dropwise 1.57M n-butyl lithium (18.8 ml, 29.6 mmol) at −78° C., and the mixture was stirred for 30 minutes. To the mixture, was added dropwise trimethyl borate (6.00 ml, 53.8 mmol), and warmed to room temperature. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added while cooling on ice, which was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-heptane/ethyl acetate=1/1) to obtain the title compound (4.97 g, 20.7 mmol)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:9])[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-chloro-phenol (2.0 g, 9.64 mmol) and anhydrous potassium carbonate (4.0 g, 28.92 mmol) in dry DMF (30 ml) was heated at 60° C. for 1 h under Ar atmosphere. The mixture was then cooled to room temperature and ethyl chloroacetate (1.24 ml, 11.57 mmol) was added through septum using syringe. The mixture was stirred overnight at room temperature and poured into water with stirring. Stirring continued for 10 min, and then partitioned between ethyl acetate and water. The organic phase washed with brine, dried (anhydrous MgSO4), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=15:3:1) to give (4-Bromo-2-chloro-phenoxy)-acetic acid ethyl ester as a colorless oil (2.98 (2.83) g, >100% yield). To (4-bromo-2-chloro-phenoxy)-acetic acid (132.8 mg, 0.5 mmol), 3-amino-benzamide (102.2 mg, 0.75 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (5 ml) was added N,N-diisopropylethylamine, redistilled (DIPEA) (0.13 ml, 0.75 mmol). The mixture was stirred overnight, and then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (CH2CH2:MeOH=10:1) to give 3-[2-(4-bromo-2-chloro-phenoxy)acetyl-amino]-benzamide as a white solid (181.4 mg, 94.6% yield).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[CH2:3][N:4]=[C:5]([NH2:28])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1.O.NN>C(O)C>[F:30][C:2]([F:1])([F:29])[CH2:3][N:4]=[C:5]([NH2:28])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][CH2:15][CH2:16][NH2:17])[N:8]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccnc(CSCCN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCSCc1nccc(NC(N)=NCC(F)(F)F)n1
Yield: 77.2 %

Procedure:
A mixture of 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-phthalimidoethyl)thiomethyl]pyrimidine (5.4 g.), ethanol (30 ml.) and 99% hydrazine hydrate (3 ml.) was heated under reflux for 1 hour and then evaporated to dryness. The residue was stirred with N hydrochloric acid and then filtered and the filtrate basified with 17N NaOH. The mixture was extracted with ether, and the ether extracts dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-[(2-aminoethyl)thiomethyl]pyrimidine (2.93 g.) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: Oc1ccccc1Br
Reactant: ClCCCBr
Product: ClCCCOc1ccccc1Br

Procedure:
Prepared by Procedure U and Scheme AK using 2-bromophenol and 1-bromo-3-chloropropane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+].CNCCS>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCSc1nc2ccccc2[nH]1)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CNCCS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(SCCCN(CCc2ccccc2)C(=O)OC(C)(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-[3-(tert-Butoxycarbonyl-phenethyl-amino)-propylsulfanyl]-benzoimidazole (Precursor J-01c, 239 mg, 0.58 mmol), tert-butyl bromoacetate (136 mg, 103 μl, 0.70 mmol) and cesium carbonate (227 mg, 0.70 mmol) are dissolved in dry DMF (6 ml) and allowed to stir for 1 h at rt. N-(2-Mercaptoethyl)aminomethyl polystyrene (1.4 mmol/g, 0.5 g, 0.36 mmol) is added and the crude mixture is stirred at rt for 1 h. After filtration and removal of the solvent in vacuo, the crude product is diluted in dichloromethane, washed with a 10% aqueous citric acid solution and with a saturated aqueous NaHCO3 solution. The organic phase is dried over MgSO4 and the solvent evaporated in vacuo, yielding the title compound: tR=2.79 min (LC-2), ESI-MS (neg.): m/z 526.61 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.46 (s, 18H, 2×tBu), 2.00 (m, 2H, SCH2CH2), 2.85 (m, 2H, CH2Ph), 3.26-3.85 (m, 6H), 4.77 (s, 2H, CH2CO2), 7.44-7.59 (m, 8Harom), 7.94 (m, 1Harom).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:26])([CH3:25])[CH2:16][CH:17]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]3=[CH:10][C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:4]([Cl:34])[CH:3]=1.[CH3:35][N:36](C=O)C>O.[C-]#N.[C-]#N.[Zn+2].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.C(Cl)(Cl)Cl.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:34][C:4]1[CH:3]=[C:2]([C:35]#[N:36])[CH:7]=[CH:6][C:5]=1[C:8]1[N:13]=[C:12]2[O:14][C:15]([CH3:25])([CH3:26])[CH2:16][CH:17]([NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:11]2=[CH:10][C:9]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3Cl)nc2O1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a suspension of the product of Step A (141 mg, 0.25 mmol), Zn(CN)2 (29.4 mg, 0.25 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (5.2 mg, 0.005 mmol), and dppf (6.9 mg, 0.01 mmol) in 5.0 mL of DMF was added one drop of H2O. The solution was degassed and stirred at 120° C. for 16 h, the reaction mixture was cooled to rt and diluted with EtOAc (20 mL). The solid was filtered off and washed with EtOAc. The filtrate was concentrated and chromatography on a Biotage 40+M cartridge using 2:3 v/v EtOAc/hexanes as the eluant afforded the title compound: 1H NMR δ 1.27 (s, 9H), 1.48 (s, 3H), 1.56 (s, 3H), 1.84 (m, 1H), 2.26 (m, 1H), 5.50 (m, 1H), 5.82 (br. s, 1H), 6.95 (d, J=8.2, 2H), 7.19 (d, J=8.3, 2H), 7.41-7.58 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[C:7](F)=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23].C(O)(=O)C.[CH:29]([NH2:31])=[NH:30]>CC(N(C)C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23])[N:31]=[CH:29][N:30]=[C:10]2[CH3:11])=[O:24]
Reactant: N=CN
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 95 °C
Yield: 47.9 %

Procedure:
A mixture of 5-acetyl-2-(4-bromo-2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (288 mg, 0.688 mmol) and formamidine acetate (77 mg, 0.74 mmol) in DMA (7 mL) was heated for 4 hours at 95° C. Additional 10 mg (0.096 mmol) of formamidine acetate was added and the reaction mixture was heated for additional 4 hours at 95° C. The reaction mixture was diluted with EtOAc, and washed with water (3×). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material which was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford the desired product (140 mg, 48%).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][CH2:10]C(O)=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH:23]=[CH2:24])[CH2:19][CH:20]=O)[CH3:15]>C1(C)C=CC=CC=1.CO>[C:1]1([C@H:7]([N:9]2[CH:20]3[CH2:19][N:18]([C:17]([O:16][CH2:14][CH3:15])=[O:25])[CH2:22][CH:23]3[CH2:24][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: C[C@@H](NCC(=O)O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)N1CC2CCN([C@H](C)c3ccccc3)C2C1
Temperature: 90 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
A solution of (1-(R)-phenyl-ethylamino)-acetic acid (25.6 g) in 384 mL of toluene was heated to 90° C. To this 170 g (1.1 equivalents) of a 15.84 wt. % solution of allyl-(2-oxo-ethyl)-carbamic acid ethyl ester (U.S. Pat. No. 5,071,999) in toluene, was added over 20 minutes and the mixture was stirred at 90° C. for 14 hours then at 95° C. for 12 hours. After cooling, the product was extracted with 2×115 g of 20% citric acid solution. The citric acid solution was diluted with 205 mL of isopropyl acetate, and the mixture was neutralized with a solution of 51.2 g K2CO3 in 120 g water, and thoroughly shaken. The layers were separated, and the aqueous layer was extracted again with 102 mL of isopropyl acetate. The organic extracts were combined and distilled under reduced pressure to provide an oil which was then diluted with 125 mL of MeOH to provide 140 g (100% yield) of the title compound as a 30% by weight solution in MeOH.