Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[CH3:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([CH3:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1cc([Mg]Br)ccc1Cl
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1Cl

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-chloro-3-methylphenylmagnesium bromide. Yield: 54 mg of a white solid. LC-MSD, m/z for C23H16BrClN2O2 [M+H]+=467.0, 469.0; HPLC retention time: 2.6 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[N:4][CH:5]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1ccncn1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccncn1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 4-(chloromethyl)pyrimidine (4.10 g, 31.9 mmol, prepared according to R. W. Carling et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) and potassium phthalimide (5.91 g, 31.89 mmol) in N,N-dimethylformamide (60 mL) was heated to 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (50 mL) and brine (50 ml). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40-50% ethyl acetate in hexanes to afford 2-(pyrimidin-4-ylmethyl)isoindoline-1,3-dione in 40% yield (3.0 g): 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.70 (br s, 1H), 7.93-7.86 (m, 2H), 7.79-7.75 (m, 2H), 7.30 (d, J=6.0 Hz, 1H), 4.99 (s, 2H); MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:17][CH:18]=1>C(O)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([N:12]3[C:1](=[O:11])[C:2]4[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=4[C:4]3=[O:6])=[CH:18][N:17]=2)=[CH:23][CH:24]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(OCCc2ccc(Cl)cc2)nc1
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(OCCc2ccc(Cl)cc2)nc1
Reaction time: 1.5 h

Procedure:
A mixture of 3,4,5,6-tetrahydrophthalic anhydride (0.4 g), 5-amino-2-(4-chlorophenethoxy)pyridine (0.6 g) and acetic acid (20 ml) is heated to reflux. After about 1.5 hours, the reaction is cooled and concentrated to about one-half volume. On standing a crystalline solid precipitation which is collected by filtration and washed with 10% ethyl acetate/hexane to yield N-[2-(4-chlorophenethoxy)-5-pyridyl]-3,4,5,6-tetrahydrophthalimide.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[CH:18]=[CH:19][CH:20]=[N:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>O1CCCC1>[CH3:29][N:30]([CH:32]=[C:14]1[CH2:15][CH2:16][N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[C:11]2[N:21]=[CH:20][CH:19]=[CH:18][C:12]=2[C:13]1=[O:17])[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ncccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a slurry of 0.50 g of 6,7,8,9-tetrahydro-9-(4-nitrobenzoyl)-5H-pyrido[2,3-b]azepin-5-one in 10 ml of tetrahydrofuran under argon is added 0.70 g of tert-butoxy-bis(dimethylamino)methane and the mixture is stirred at room temperature overnight. The volatiles are removed under vacuum and the residue in ethyl acetate-CH2Cl2 (2:8) filtered through a short column of silica gel. The silica gel is washed with ethyl acetate (discard) and then with chloroform containing 3% methanol to give 0.51 g of the product as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=3)[C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2].[C:29](Cl)(=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]2[O:12][C:11](=[O:13])[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:29](=[O:47])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:16][CH:15]=3)[C:9]=2[CH:24]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2c1ccc(OCCO)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1
Yield: 88.9 %

Procedure:
A suspension of 11.4 g (30 mmol) of 5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]ben-zofuran-2-one (compound (105), Example 3) and 9.4 g (31 mmol) of stearoyl chloride in 60 ml of toluene is refluxed for 4 hours. The reaction mixture is then concentrated on a vacuum rotary evaporator, and the residue is recrystallized from methanol to give 17.3 g (89%) of 5,7-di-tert-butyl-3-[4-(2-stearoyloxyethoxy)phenyl]benzofuran-2-one, m.p. 54°-60° C. (compound (107), Table 1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:12])[C:10]#[N:11])[CH3:2].[CH2:13](N)[CH2:14][NH2:15]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:10]1[NH:11][CH2:13][CH2:14][N:15]=1)[CH3:12])[CH3:2]
Reactant: NCCN
Reactant: CCc1ccccc1C(C)C#N
Product: CCc1ccccc1C(C)C1=NCCN1

Procedure:
rac-2-[1-(2-Ethyl-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2-ethyl-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid;
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[CH2:21]1[CH2:26][O:25][CH:24]=[CH:23][CH2:22]1>>[O:25]1[CH2:26][CH2:21][CH2:22][CH2:23][CH:24]1[O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: C1=COCCC1
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O

Procedure:
The THP ether 60, which was prepared from estrone 1 (6.3 g, 23.3 mmol) and DHP (3.0 g, 33 mmol) using the same procedure as described for compound 35, was obtained as a white solid (7.5 g, 91%): 1H NMR (300 MHz, CDCl3) δ0.91 (s, 3, CH3), 2.89 (m, 2), 3.60 (m. 1), 3.92 (m, 1), 5.40 (m, 1), 6.81 (d, J=2.5 Hz, 1, ArH), 6.86 (dd, J=2.5, 8.5 Hz, 1, ArH), 7.20 (d, J=8.5 Hz, 1, ArH).
Reaction SMILES: B(Br)(Br)Br.[OH:5][C:6]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:19]C.O>C(Cl)Cl>[OH:19][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:6]=1[OH:5])[C:10]([OH:12])=[O:11]
Reactant: COc1cc(C(=O)O)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1cc(O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 69.7 %

Procedure:
Boron tribromide (392 μL, 4.15 mmol) was added to a suspension of 4-hydroxy-3-methoxy-5-(trifluoromethyl)benzoic acid (4) (392 mg, 1.66 mmol) in DCM (10 mL) at 0° C. The reaction mixture was allowed to warm to RT and stirred for 70 h. The reaction mixture was cautiously added to stirring iced water (50 mL) and stirred for 10 min. The product was extracted with DCM (2×20 mL), and then the combined organic extracts were washed with brine (2×20 mL). The solvent was removed in vacuo and the residue was purified by silica chromatography (12 g, 0-10% MeOH in DCM) to afford 3,4-dihydroxy-5-(trifluoromethyl)benzoic acid (5) (257 mg, 68%) as a white solid: m/z 221 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.83 (1H, br s), 10.45 (2H, br d), 7.56 (2H, dd).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]2=[O:17])=[CH:4][CH:3]=1.C(NC1C=CC([O:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([O:42][Si](C(C)(C)C)(C)C)[CH2:38][CH2:37]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O.Cl>[CH3:16][C:11]1([CH3:15])[CH2:12][C:13](=[O:14])[N:8]([C:5]2[CH:6]=[N:7][C:2]([O:1][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]3)=[O:33])=[CH:3][CH:4]=2)[C:9](=[O:17])[CH2:10]1
Reactant: CC1(C)CC(=O)N(c2ccc(O)nc2)C(=O)C1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCC(O)CC3)nc2)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.2 %

Procedure:
A solution of 6′-hydroxy-4,4-dimethyl-4,5-dihydro-3H-[1,3′]bipyridinyl-2,6-dione (468 mg, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, filtered over a short pad of silicagel and washed with ethyl acetate. The solvent was evaporated in vacuo and the residue was dissolved in 1N HCl in ethyl acetate (10 mL, 10.0 mmol). After stirring for 1.5 hours at room temperature the solvent was evaporated in vacuo. The white solid was washed with a small amount of ethyl acetate and diethyl ether and dissolved in a few millilitres of dichloromethane and triethylamine (1 mL). Purification by flash column chromatography (SiO2, ethyl acetate:acetone 90:10) yielded the title compound (182 mg, 25% yield) as a white solid.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[C:8]1=[O:17]>CC(C)=O>[I:1][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH3:16])[C:8]1=[O:17]
Reactant: [I-]
Reactant: Cn1c(=O)n(CCCCl)c2ccccc21
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1c(=O)n(CCCI)c2ccccc21
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Sodium iodide (3.43 g, 22.89 mmol, 2 equiv) was added to a solution of 1-(3-chloropropyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (2.57 g, 11.44 mmol, 1 equiv) in acetone. The reaction mixture was refluxed for 16 h. After cooling to ambient temperature, it was evaporated under reduced pressure to remove all the acetone. The residue was worked up using ethyl acetate and water, followed by a wash with brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a red oil (3.62 g, quant); 1H NMR (400 MHz, DMSO-d6): δ 2.12-2.19 (m, 2H); 3.24 (t, 2H, J=7.2 and 6.8 u Hz); 3.28 (s, 3H); 3.89 (t, 2H, J=6.8 Hz); 7.04-7.09 (m, 2H); 7.13-7.16 (m, 1H); 7.18-7.22 (m, 1H); MS for C11H13IN2O m/z 316.89 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>CN1C(=O)CCC1.[N+](C1C=CC=CC=1)([O-])=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:18]([C:16]3[S:17][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: Nc1cc(Cl)cnc1N
Solvent: CN1CCCC1=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2nc3cc(Cl)cnc3[nH]2)s1
Temperature: 170 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
5-Chloropyridine-2,3-diamine (4.0 g, 28 mmol) was dissolved in NMP (3 ml) and heated to 170° C. 5-Nitrothiophene-2-carbaldehyde (4.4 g, 28 mmol) dissolved in nitrobenzene (3 ml) and NMP (2 ml) was added slowly over 30 min. After 3 h, the reaction mixture was diluted with EtOAc and purified by dry flash chromatography (0%, 10%, 50%, 70% EtOAc in toluene), giving the title product (2 g, 25%).
Reaction SMILES: [C:1]1(=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][C:3](=[O:12])[NH:2]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[H-].[Na+]>CN(C=O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:2]1[C:3](=[O:12])[CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:1]1=[O:13]
Reactant: O=C1CCc2ccccc2C(=O)N1
Reactant: BrCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2C(=O)N1CCCCCBr
Reaction time: 1.5 h
Yield: 58.9 %

Procedure:
In 20 ml of DMF was dissolved 100 mg of 1,3,4,5-tetrahydro-2-benzazepine-1,3-dione and the solution then ice-cooled. Then, to the resulting solution were added 0.117 ml (1.5 equivalent) of 1,5-dibromopentane and 27.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 109 mg (yield: 58.9%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:20]#[N:21].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:9]2)=[N:7][C:2]=1[NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)#[N:21]
Reactant: Nc1ccc(F)cc1
Reactant: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN(C)C(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Nc3ccc(F)cc3)n2)C1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
(R)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (222, 40 mg, 0.13 mmol), 4-fluoroaniline (29 mg, 0.26 mmol), fine-powder cesium carbonate (170 mg, 0.52 mmol), Pd(OAc)2 (10 mg, 0.04 mmol), BINAP (25 mg, 0.04 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 mM It was then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. The mixture was cooled to RT, diluted with 60 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 7% MeOH in chloroform to isolate (R)-3-(1-(5-cyano-6-(4-fluorophenylamino)pyrazin-2-yl)piperidin-3-yl)-1,1-dimethylurea (223). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1.5 hour, diluted with 10 mL MeCN, stirred for 5 mM, concentrated in vacuo, acidified with 0.2 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide (224) as HCl salt (40 mg, 76%). MS found for C19H24FN7O2 as (M+H)+ 402.1, (M−H)− 400.1. UV: λ=264, 274, 300, 331, 372 nm. Proton NMR (CD3OD): δ 7.63 (1H, s), 7.59 (2H, m), 7.02 (2H, t, J=9.0 Hz), 4.34 (1H, m), 4.19 (1H, m), 3.74 (1H, m), 3.17 (1H, m), 3.05 (1H, m), 2.89 (6H, s), 2.02 (1H, m), 1.86 (1H, m), 1.70-1.61 (2H, m) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.P(Br)(Br)[Br:15]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([Br:15])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: BrP(Br)Br
Product: O=C(Br)c1ccc(C(F)(F)F)cc1
Yield: 169.7 %

Procedure:
In a 50 ml glass reactor, 30 g of 4-trifluoromethylbenzoic acid and 14.5 g of phosphorus tribromide were reacted at 155° C. for 3 hr. After that the reaction liquid was distilled under reduced pressure to obtain 23 g of 4-trifluoromethylbenzoyl bromide having a boiling point of 88°-89° C. at 18 mmHg. The yield in this reaction was 58%.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26](O)=O)[CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O1CCOCC1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=3)[N:12]=2)[CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: COc1ccc(C(=N)NO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Product: COc1ccc(-c2noc(C3CCCN(C(=O)OC(C)(C)C)C3)n2)cc1
Temperature: 80 °C
Yield: 0.1 %

Procedure:
A mixture of N-Hydroxy-4-methoxy-benzamidine (0.20 g, 1.50 mmol), 1-Boc-piperidine-3-carboxylic acid (0.34 g, 1.50 mmol), HOBT (0.23 g, 1.50 mmol) and EDCI.HCl (0.43 g, 2.25 mmol) in dioxane (2.5 ml) was stirred at R.T for 7H. After this time the mixture was heated at 80° C. overnight with the carousel Radley's. The mixture was concentrated. The organic layer was washed with water, NaOH 1N and water. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography (DCM/MeOH: 99/1) to afford 0.39 mg (72%) of 3-[3-(4-Methoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester as white solid.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[N:25]2[C:33](=[O:34])[CH:28]3[CH2:29][NH:30][CH2:31][CH2:32][N:27]3[C:26]2=[O:35])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:30]1[CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:33](=[O:34])[CH:28]2[CH2:29]1)=[O:9]
Reactant: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1-c1ccccc1)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
[1,1′-Biphenyl]-2-yl-isocyanate (1.1 eq) was added to a stirred solution of A5 and DIPEA (3.0 eq) in DCM (0.09 M), and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 76% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.36 (1H, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, m), 4.19 (1H, m), 3.93 (1H, m), 3.85-3.77 (2H, m), 2.86 (1H, m), 2.74 (2H, d, J=9.3 Hz), 2.67 (1H, m), 2.40-2.30 (1H, m), 1.58-1.48 (1H, m), 1.43-1.37 (1H, m). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.O>C(Cl)Cl>[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]=1)=[O:14]
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Reactant: CC1CCCCN1
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CC1CCCCN1C(=O)c1csc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-phenyl-thiophene-3-carboxylic acid (1 eq.) in DCM (1 mL/100 mg SM) was added EDC (1.5 eq.). This mixture was stirred at room temperature for 5 minutes and then 2-methyl piperidine (1.2 eq.) was added and the mixture stirred for 18 hours. Water (1 mL/100 mg SM) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane). LCMS m/z 286 [M+H]+ R.T.=3.85 min (Analytical Method 3).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1>O1CCCC1>[CH3:45][N:42]1[CH2:43][CH2:44][N:39]([NH:38][CH2:2][C:3]2[CH:31]=[CH:30][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:29])=[C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:20]=[CH:19][N:18]=4)[CH:15]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC(=O)c2ccc(CCl)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCN(N)CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CNN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
N-[5-(4-chloromethylbenzoylamino)-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidine-amine (1 g, 2.33 mmol) was dissolved in tetrahydrofuran (20 ml), pyridine (360 μl, 4.66 mmol) was added thereto, and the mixture was stirred for 30 minutes. 1-Amino-4-methylpiperazine (418 μl, 3.49 mmol) was added, and the mixture was refluxed for 12 hours and filtered. The filtrate was concentrated, subjected to column chromatography (eluent: chloroform:methanol=3:1(v/v)), concentrated again, and then crystallized from dimethylether to give 4-(4-methylpiperazin-1-ylaminomethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-yl)aminophenyl]benzamide (880 mg).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][C:10]([F:30])=[C:11]([C@@:13]34[O:21][CH2:20][CH2:19][C@@H:18]3[CH2:17][S:16][C:15]([NH:22]C(=O)OC(C)(C)C)=[N:14]4)[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][C:10]([F:30])=[C:11]([C@@:13]34[O:21][CH2:20][CH2:19][C@@H:18]3[CH2:17][S:16][C:15]([NH2:22])=[N:14]4)[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC4CCCC4)ccc3F)OCC[C@@H]2CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1=N[C@]2(c3cc(NC4CCCC4)ccc3F)OCC[C@@H]2CS1
Yield: 137 %

Procedure:
A solution of tert-butyl (±)-((4aS,7aS)-7a-(5-(cyclopentylamino)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (16 mg, 0.037 mmol) and TFA (56.6 μL, 0.735 mmol) in DCM (245 μL) was stirred at rt for 3 h. The solvents were removed to give (4aS,7aS)-7a-(5-(cyclopentylamino)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-amine (17 mg) as its TFA salt as a colorless oil. MS (M+H)+: 336.02.