Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+].Br[C:78]1[CH:83]=[C:82]([F:84])[C:81]([F:85])=[CH:80][C:79]=1[O:86][CH3:87]>CC(O)=O.CC(O)=O.[Pd].C(#N)C>[F:85][C:81]1[C:82]([F:84])=[CH:83][C:78]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)=[O:29])=[C:79]([O:86][CH3:87])[CH:80]=1
Reactant: COc1cc(F)c(F)cc1Br
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Pd]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Cs+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)c(F)cc3OC)ccc2c1

Procedure:
Add trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.3 gm, 4.2 mmoles), bis(pinacolato)diboron (1.3 gm, 5.1 mmoles), palladium II acetate (97 mg, 0.4 mmoles), triphenylphosphine (222 mg, 0.84 mmoles) and cesium fluoride (2.1 gm, 14.1 mmoles) in a 250 ml round bottom flask under nitrogen and add 100 ml of anhydrous acetonitrile. Stir and heat to reflux for 2 hours. Allow the mixture to cool and to this mixture add 2-bromo-4,5-difluoroanisole (2.8 gm, 12.5 mmoles), palladium II acetate (96 mg, 0.43 mmoles) triphenylphosphine (222 mg, 0.84 moles) and cesium fluoride (1.8 gm, 12.2 mmoles). Reflux the mixture for 18 hours and filter through Celite. Evaporate the solvent and pass through an SCX column eluting the product with 2N ammonia/methanol. The product is purified on a silica column eluting with a gradient of 25% THF/hexane to 5% 2N ammonia/methanol in 25% THF/Hexane. LC/MS gives a peak with the proper mass.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH2:25]([C:27]1[CH:28]=[N:29][C:30](Cl)=[N:31][CH:32]=1)[CH3:26].CCN(C(C)C)C(C)C>C(O)(C)C>[CH2:25]([C:27]1[CH:28]=[N:29][C:30]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:32]=1)[CH3:26]
Reactant: CCc1cnc(Cl)nc1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 5-ethyl-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 454.02 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCc1ccccc1)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 72.6 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (405 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (4 ml) and dichloromethane (4 ml). 1-Hydroxy-7-azabenzotriazole (227 mg, 1.66 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (319 mg, 1.66 mmol) was added. The solution was stirred at 0° C. for 40 min. A solution of (2R)-N-methyl-2-methylamino-3-(2-naphthyl)-N-(3-phenylpropyl)propionamide (600 mg, 1.66 mmol) in dichloromethane (4 ml) was added. Ethyldiisopropylamine (0.29 m., 1.66 mmol) was added. The solution was stirred for 2 days, while it was slowly warming up to room temperature. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with 1N hydrochloric acid (100 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crued product was purified by flash chromatography on silica (180 g), using ethyl acetate/hepaten (1:1) as eluent to give 706 mg of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-(3-phenylpropyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23]>C1C=CC=CC=1.CCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following a procedure similar to that described in Example 42 but using 2.3 g. sodium in 250 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 20.4 g. 3,4-dichlorophenyl isothiocyanate (b.p. 149-152/15-16 mm.) in 150 ml. dry acetone there was obtained 1-(3,4-dichlorophenyl)-3-(heptanimidoyl)-2-thiourea, m.p. 89°-90°C. (from benzene-n-pentane); hydrochloride (27 g.), m.p. 158°-160°C. (from acetonitrile).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCOC(C)=O.[C:44]([NH:47][CH2:48][CH2:49]O)(=[O:46])[CH3:45]>C1COCC1>[C:44]([NH:47][CH2:48][CH2:49][O:12][C:11](=[O:13])[CH:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=1)[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:25])[F:1])[CH:4]=1)(=[O:46])[CH3:45]
Reactant: O=C(O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NCCOC(=O)C(Cc1cccc(C(F)(F)F)c1)c1ccc(C(F)(F)F)cc1
Temperature: 23.5 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
3-(3-Trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)-propionic acid (105, 2.43 g, crude) was dissolved in anhydrous THF (6 mL) at ambient temperature. CDI (1.64 g, 10.1 mmol) was charged as a solid, followed by EtOAc (4 mL), to rinse the vial. The internal temperature remained between 20-21° C. during the addition. N-acetylethanolamine (3.6 mL, 39 mmol) was added, whereupon the temperature rose to 24.5° C. The mixture was stirred overnight (16 h) at 23-24° C. and then rotary evaporated to a gummy residue. This was chromatographed on silica gel using EtOAc: hexane (70:30 v/v) (Rf=0.35-0.40) to afford 2-acetamidoethyl-3-(3-trifluoromethylphenyl)-2-(4-trifluoromethylphenyl)propionate 105A (1.85 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:38])OC(C)(C)C)[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:40][C:41](=[O:60])[CH2:42][C@H:43]([NH:47][C:48]([C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]=1)=[O:49])C(O)=O.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>FC(F)(F)C(O)=O.CN(C)C=O>[CH2:1]([C@H:8]([NH:31][C:32](=[O:38])[C@@H:43]([NH:47][C:48]([C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[N:51]=1)=[O:49])[CH2:42][C:41]([NH2:40])=[O:60])[C@@H:9]([OH:30])[CH:10]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[O:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)NC(OC2CCCCC2)[C@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)c2ccc3ccccc3n2)cc1
Reaction time: 15 h

Procedure:
tert-butyl N-((1S,2R)-1-benzyl-3-(cyclohexyloxy)[(4-methoxyphenyl)sulfonyl]amino-2-hydroxypropyl)carbamate (0.18 mmol, 100 mg) was stirred in 1 mL trifluoroacetic acid (TFA) at room temperature for 1 hour. The TFA was removed under vacuum, and the resulting residue was dissolved in ethyl acetate, washed with 5% aq. potassium carbonate solution, brine, dried over magnesium sulfate, and concentrated to a residue. The resulting free amine, (2S)-4-amino-4-oxo-2-[(2-quinolinylcarbonyl)amino]butanoic acid hydrochloride (0.18 mmol, 56 mg), 1-hydroxybenzotriazole hydrate (0.18 mmol, 25 mg), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.20 mmol, 38 mg), diisopropylethylamine (0.91 mmol, 0.157 mL) and anhydrous N,N-dimethylformamide (0.5 mL) were combined at room temperature and stirred for 15 hours. The crude reaction mixture was concentrated to a residue, dissolved in ethyl acetate, washed with 1N HCl, 5% aq. potassium carbonate solution, brine and dried over magnesium sulfate. The solution was concentrated to a residue, purified by silica gel chromatography (ethyl acetate), and lyophylized providing a fluffy white solid. H-1-NMR (CDCl3): δ 9.19-9.17 (1H,m), 8.32-8.30 (1H,m), 8.23-8.16 (2H,m), 7.89-7.87 (1H,m), 7.79-7.76 (3H,m), 7.65-7.61 (1H,m), 7.13-7.11 (2H,m), 7.05-6.94 (6H,m), 5.73-5.64 (1H,m), 5.41-5.33 (1H,m), 4.96-4.85 (1H,m), 4.28-4.08 (2H,m), 3.89-3.74 (1H,m), 3.86 (3H,s), 3.25 (1H,bs), 2.95-2.79 (5H,m), 2.65-2.60 (1H,m), 2.04 (2H,bs), 1.70 (2H,bs), 1.57-1.41 (1H,m), 1.30-1.10 (5H,m); MS (ESI): M+H=719.
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:21]1([C:27]2[NH:36][C:30]3[N:31]=[CH:32][N:33]=[C:34]([SH:35])[C:29]=3[CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[N+:7]([C:4]1[S:3][C:2]([S:35][C:34]2[C:29]3[CH:28]=[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:36][C:30]=3[N:31]=[CH:32][N:33]=2)=[CH:6][CH:5]=1)([O-:9])=[O:8]
Reactant: Sc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ncnc3[nH]c(-c4ccccc4)cc23)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After adding 1.05 g of 2-bromo-5-nitrothiophene, 0.95 g of potassium carbonate and 15 ml of dimethylformamide to the 6-phenyl-7H-pyrrolo[2,3-d]pyrimidine-4-thiol synthesized in Production Example 161-1 and stirring the mixture overnight at room temperature, water was added and the precipitated crystals were filtered out, blow-dried and dried under reduced pressure to obtain 1.30 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7]([NH:14][CH:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[CH:6][C:5]=1[CH3:21]>O1CCOCC1>[F:20][C:17]1([F:19])[CH2:16][CH:15]([NH:14][C:7]2[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([CH3:21])[CH:6]=2)[CH2:18]1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(NC2CC(F)(F)C2)cc1C
Solvent: C1COCCO1
Product: Cc1cc(NC2CC(F)(F)C2)c(S(C)(=O)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
210 mg of 4-(3,3-Difluoro-cyclobutylamino)-5-methanesulfonyl-2-methyl-benzoic acid methyl ester were dissolved using 10 ml of dioxane, and 0.47 ml of a 2N aqueous NaOHsolution was added. The mixture was stirred for 18 h at ambient temperature. Afterwards, the solvents were removed in vacuo. The residue was then taken up using 10 ml of water. The pH was adjusted to pH=2 using an aqueous HClsolution and extracted three times using 20 ml of EE each time. The organic layer was dried over MgSO4 and the solvent removed in vacuo. Yield: 196 mg of an amorphous solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O)(C)(C)C.Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[NH2:8])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccsc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
Treat dropwise a solution of (tert-butoxy)-N-[2-(4-bromophenyl)(3-thiophenyl)]carboxamide (10.8 g, 0.3 mol) in EtOAc (75 mL) at 0° C. with 244 mL (8 mL/mmol) of freshly prepared 1N HCl in EtOAc and stir the mixture at room temperature overnight. Dissolve the white precipitate with H2O (100 mL) and neutralize with a NaHCO3 saturated solution. Extract the mixture with EtOAc (3×100 mL) and combine organic, dry and concentrate to give a slightly colored solid. Purification of the crude material by flash chromatography (Silica gel-Hexane/AcOEt 49:1 then 9:1) furnishes 5.7 g (74%) of 2-(4-bromo-phenyl)-thiophen-3-yl amine as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7].I[CH3:20]>C1COCC1>[Br:3][C:4]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([N:8]([CH3:20])[CH2:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:7]
Reactant: CI
Reactant: Cc1cccc(C(=O)NCC(C)(C)C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)N(C)CC(C)(C)C)c1Br
Reaction time: 0.33 h

Procedure:
To a slurry of NaH (60% in mineral oil) (0.122 mL, 2.81 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-3-methyl-N-neopentylbenzamide (400 mg, 1.407 mmol) in THF (1 ml) at RT. After 20 min, iodomethane (0.096 mL, 1.548 mmol) was added and the reaction was allowed to stir for 48 h. The reaction was quenched by the addition of water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (6-48% EtOAc/hexanes). 2-Bromo-N,3-dimethyl-N-neopentylbenzamide was isolated as a clear colorless viscous oil.
Reaction SMILES: [CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC3OCCOC=3C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(C=CN2)=CC=1>>[CH2:1]1[CH2:10][O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:21]=[C:22]5[C:23]([CH:31]=[CH:30][NH:29]5)=[CH:24][CH:25]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Agent: Nc1ccc2cc[nH]c2c1
Product: Fc1cnc(Nc2ccc3cc[nH]c3c2)nc1Nc1ccc2c(c1)OCCO2

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 6-aminoindole were reacted to yield N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 20.80 min.; purity: 91%; MS (m/e): 378 (MH+).
Reaction SMILES: [I-].Br[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N+:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[C:6]2([CH3:16])[CH3:15].[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>[Ni](Cl)Cl.CO>[CH2:17]([O:19][P:20]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[CH2:14])[C:6]2([CH3:16])[CH3:15])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CC[N+]1=C(C)C(C)(C)c2cc(Br)ccc21
Reactant: CCOP(OCC)OCC
Agent: Cl[Ni]Cl
Agent: [I-]
Solvent: CO
Product: C=C1N(CC)c2ccc(P(=O)(OCC)OCC)cc2C1(C)C
Temperature: 175 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To a 250 mL flask were added 3 (9.6 g, 20 mmol) and nickel chloride (0.52 g, 4.0 mmol). The flask was fitted with a dropping funnel and a condenser and was then lowered into an oil bath. The mixture was heated to 175° C. At approx. 165° C. triethylphosphite (15 mL, 86 mmol) was added dropwise. The mixture fizzed and became dark before turning to a dark straw color. After heating at 175° C. for 30 min a second portion of nickel chloride (0.52 g, 4.0 mmol) was added. The mixture fizzed vigorously, gave off much vapor and became dark grey-green in color. Heating was continued for 30 min and then the reaction was cooled to rt. The mixture was treated with methanol (100 mL) and filtered through a bed of celite. The methanol was evaporated in vacuo to leave an oil that was fractionally distilled on a KUGELROHR® vacuum distillation apparatus to afford 5 as a colorless liquid (4.0 g, 62%). The oil was stored under argon.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35](CC2C=CC(OC)=CC=2)[C:36](=[O:38])[CH3:37])[CH:30]=1)#[N:2].C(O)(=O)C.FC(F)(F)S(O)(=O)=O.C(Cl)Cl>C(#N)C.O.C(=O)=O.CO.C(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:18]=[CH:19][N:20]=2)[S:5][C:4]=1[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C:36](=[O:38])[CH3:37])[CH:30]=1)#[N:2]
Reactant: COc1ccc(CN(C(C)=O)c2cc(-c3sc(-c4nccn4Cc4ccc(F)cc4)c(-c4ccc(Cl)cc4Cl)c3C#N)ccn2)cc1
Agent: O=C=O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CC(=O)Nc1cc(-c2sc(-c3nccn3Cc3ccc(F)cc3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.1 %

Procedure:
To the solution of [A] N-(4-{3-cyano-4-(2,4-dichlorophenyl)-5-[1-(4-fluorobenzyl)-1H-imidazol-2-yl]-2-thienyl}pyridin-2-yl)-N-(4-methoxybenzyl)acetamide (55.0 mg, 0.0806 mmol) in Acetic acid (1.0 mL, 18 mmol) was added Trifluoromethanesulfonic acid (0.10 mL, 1.1 mmol) and the mixture was stirred at r.t. for 20 hours. Methylene chloride (2.0 mL, 31 mmol) and Trifluoromethanesulfonic acid (0.10 mL, 1.1 mmol) were added and the mixture was stirred at r.t. for 20 hours. The mixture was rotovaped and azeotropped with toluene twice, dried in high vacuum. The residue was neutralized with aqueous saturated NaHCO3 to pH˜8, extracted with EtOAc. The EtOAc solution was dried over Na2SO4, filtered, evaporated in rotavapor to give a crude residue. Chromatograph in a silica column using MeOH/DCM (0/100 to 2/98) afforded a solid product. The product was dissolved in small amount of acetonitrile and ˜5 mL water, frozen in dry ice and lyophilized to give a powder product (20 mg, yield 44.1%). LCMS: (AA) ES+, 562, 564; FS−, 560, 562. 1H NMR (400 MHz, d1-methanol) δ: 8.62 (s, 1H), 8.47-8.48 (d, J=5.27 Hz, 1H), 7.53-7.55 (dd, J=5.27, 1.76 Hz, 1H), 7.47 (d, J=2.01 Hz, 1H), 7.33-7.36 (dd, J=8.28, 2.01 Hz, 1H), 7.26-7.27 (d, J=8.28 Hz, 1H), 7.16-7.19 (dd, J=7.28, 1.51 Hz, 2H), 6.98-7.02 (m, 2H), 6.83-6.86 (m, 2H), 4.98 (s, 2H), 2.21 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](CBr)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][S-:14].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:14][CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: C[S-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 60 h
Yield: 105.8 %

Procedure:
A suspension of 4-bromo-1-(bromomethyl)-2-nitrobenzene (1.0 g) and sodium methanethiolate (0.285 g) in tetrahydrofuran (20 ml) was stirred under nitrogen for 60 h. The solvent was evaporated, chloroform (50 ml) was added and the rsidual solid was removed by filtration. The filtrate was comncentrated under vacuum to give the title compound (0.89 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1.C(O)(=O)C(O)=[O:16].O1CCOCC1>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:16])([OH:12])[CH3:13]
Reactant: Clc1ccc(CCC2CO2)c(Cl)c1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(O)(O)CCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 50 parts of [2-(2,4-dichlorophenyl)ethyl]-oxirane, 7 parts of ethanedioic acid, 300 parts of 1,4-dioxane and 150 parts of water is stirred and refluxed for 36 hours. The reaction mixture is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried at the air, yielding 1-[2-(2,4-dichlorophenyl)ethyl]ethanediol; mp. 83.2°C.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[CH2:7]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22](=O)[CH2:23][C:24](=O)[CH3:25])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[CH:23]=[C:24]([CH3:25])[N:3]=[C:4]([NH2:6])[N:5]=1)=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N=C(N)N
Reactant: CC(=O)CC(=O)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C2CCCN2C(=O)OCc2ccccc2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.5 %

Procedure:
Sodium (550 mg, 25.0 mmol) was added portionwise to a stirred solution of anhydrous ethanol (30 mL) under nitrogen at room temperature. When all the sodium had dissolved, to the solution was added a solution of guanidine hydrochloride (2.28 g, 25.0 mmol) in ethanol (20 mL). The resulting mixture was stirred for 20 minutes. The precipitated sodium chloride was removed by filtration and to the clear filtrate was added 2-(3-oxo-butyryl)-pyrrolidine-1-carboxylic acid benzyl ester (6.87 g, 23.7 mmol). The flask was then fitted with a Dean-Stark Tube and 20 mL of distillate was removed as the solution was heated to reflux under nitrogen for 12 h. The mixture was allowed to cool to room temperature, then was gradually cooled to −5° C. The resulting solid was collected by filtration and air dried to give 3.37 g (46%) of 2-(2-amino-6-methyl-pyrimidin-4-yl)-pyrrolidine-1-carboxylic acid benzyl ester as cream colored crystals. [M+H]+ 312.88.