Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH2:50])=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[C:34]([CH3:51])[CH:33]=[CH:32][N:31]=1>C(#N)C>[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH:50][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[C:34]([CH3:51])[CH:33]=[CH:32][N:31]=1
Reactant: [N-]=C=S
Reactant: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1N
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccnc(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Temperature: 60 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To acetonitrile (50 mL) was added sodium isothiocyanate (0.1469 g, 1.813 mmol), pyridine (0.3141 ml, 3.884 mmol), followed by (R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (0.4626 g, 1.554 mmol) and the resulting mixture was heated to 60° C. for 30 minutes. 3-(2,4-Dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.500 g, 1.295 mmol) was added and the reaction was stirred overnight at 60° C. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1N NaOH. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified over silica gel (100% ethyl acetate). Concentration of the major UV component with an Rf of 0.5 afforded (S)—N-(3-(2,4-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.360 g, 0.6561 mmol, 50.7% yield) as a light yellow powder.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2OCC#N.[N-:28]=[N+:29]=[N-:30].[Na+].[NH4+:32].[Cl-]>CN(C=O)C>[O:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[CH:2]([O:1][CH:5]([C:4]1[NH:32][N:30]=[N:29][N:28]=1)[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:2]3[O:1][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[CH:3]=3)[CH:11]=2)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=1)[C:3]1[NH:32][N:30]=[N:29][N:28]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(C(OC(c2nnn[nH]2)c2cc(C(F)(F)F)nc3ccc(-c4cc5ccccc5o4)cc23)c2nnn[nH]2)c2cc(-c3cc4ccccc4o3)ccc2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 118.8 %

Procedure:
To a stirred solution of {[6-(1-benzofuran-2-yl)-2-(trifluoromethyl)quinolin-4-yl]oxy}acetonitrile (0.200 g, 0.543 mmol) in DMF (10 mL) at room temperature was added sodium azide (0.177 g, 2.72 mmol) followed by NH4Cl (0.145 g, 2.72 mmol). The reaction was heated to 100° C. for 2 hours. The mixture was concentrated and diluted with 2 N HCl (˜5 mL). This mixture was stirred at room temperature for 1 hour. The solid which formed was filtered and then washed with excess H2O and hexane and dried under high vacuum to afford the product (0.173 g, 78%) as a yellow solid, mp>225° C. (dec.), mp>225° C. (dec.). Mass spectrum (+APCI, [M+H]+) m/z 412. 1H NMR (500 MHz, DMSO-d6): δ 15.44-17.96 (br s, 1H), 8.72 (d, 1H, J=2.0 Hz), 8.46 (dd, 1H, J=2.0, 9.0 Hz), 8.21 (d, 1H, J=8.8 Hz), 7.70-7.75 (m, 3H), 7.76 (s, 1H), 7.38 (t, 1H, J=7.7 Hz), 7.30 (t, 1H, J=7.9 Hz,), and 6.04 ppm (s, 2H). Elemental analysis for C20H12F3N5O2.0.5H2O: Calculated: C, 57.15; H, 3.12; N, 16.66. Found: C, 57.43; H, 2.72; N, 16.53.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1.Cl[C:21]([F:27])([F:26])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([CH2:8][C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH:21]([F:27])[F:26])[CH:16]=[CH:17][C:11]=3[CH:10]=2)[CH:7]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc2cc(Cc3cc(Br)ccc3Cl)sc2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
5-Bromo-2-chloro-1-(6-hydroxybenzo[b]thiophen-2-ylmethyl)-benzene (1.8 g) obtained in Reference Example 132-(1) was dissolved in dimethylformamide (15 ml), and added thereto were methyl 2-chloro-2,2-difluoroacetate (1.63 ml) and potassium carbonate (2.28 g), and the mixture was stirred at 100° C. for 1.5 hours under argon atmosphere. The reaction mixture was acidified with 2N aqueous HCl solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 5-bromo-2-chloro-1-(6-difluoromethoxybenzo[b]thiophen-2-yl-methyl)benzene (695 mg) as a colorless solid. GC-Mass m/Z 402/404 (M+).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Mg]Br)(C)C.C([Si](C)(C)[C:27]1[CH:36]=[C:35]2[C:30]([C:31]([CH3:44])=[C:32]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[CH:33](O)[O:34]2)=[CH:29][CH:28]=1)(C)(C)C.Cl.[O:48]1CCCC1>CO>[CH3:44][C:31]1[C:30]2[C:35](=[CH:36][C:27]([OH:48])=[CH:28][CH:29]=2)[O:34][CH:33]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[C:32]=1[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Reactant: C1CCOC1
Reactant: CC1=C(c2ccncc2)C(O)Oc2cc([Si](C)(C)C(C)(C)C)ccc21
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: CO
Product: CC1=C(c2ccncc2)C(c2ccc(OCCN3CCCCC3)cc2)Oc2cc(O)ccc21
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(piperidin-1-yl)-ethoxy]-iodobenzene (2.56 g, 7.73 mmol, 3 eq), in tetrahydrofuran (10 mL) under argon at −78° C. was added dropwise isopropylmagnesium bromide (3.6 mL of 2.13 M, 7.73 mmol, 3 eq). The reaction mixture was then stirred for 2 hours at about −78° C. A tetrahydrofuran solution of 7-(tert-butyl-dimethyl-silanyl)-4-methyl-3-pyridin-4-yl-2H-chromen-2-ol (950 mg, 2.58 mmol, 1 eq, in 5 mL), prepared as in Example 27, was then added, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature overnight. After about 18 hours, the reaction was worked-up with addition of saturated ammonium acetate solution (15 mL) and extraction with ethyl ether (2×). The combined organic extracts were washed with brine and water, dried with anhydrous sodium sulphate, filtered and evaporated to yield a sticky semisolid residue. To this solid in THF at room temperature was added 0.5 mL HCl in MeOH. The mixture was stirred for 30 min and quenched with sat. NaHCO3, partitioned between CH2Cl2 and water. The aqueous layer was extracted 3× with CH2Cl2. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the crude material. The title product was isolated as a viscous, colorless, semisolid foam via chromatography on silica gel eluted with 3% methanol/dichloromethane.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([OH:20])=[C:8]([CH:21]=[O:22])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:10]([F:19])[C:9]([O:20][CH:2]([CH3:4])[CH3:3])=[C:8]([CH:21]=[O:22])[CH:7]=1
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C=O)cc(Br)c(-c2ccc(F)cc2)c1F
Reaction time: 3 h
Yield: 94.1 %

Procedure:
2-Iodopropane (21.7 g) was added to a mixture of 6-bromo-2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (26.7 g) and potassium carbonate (23.6 g) in DMF (250 mL) at room temperature. The mixture was stirred at 60 C under nitrogen atmosphere for 3 hours. The mixture was quenched with water at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.5 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: CC(C)OC(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)OC(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and isopropyl chloroformate to give isopropyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 1.14-1.22 (m, 6H), 2.09 (br s, 3H), 3.05 (t, J=4.4 Hz, 4H), 3.27-3.31 (m, 4H), 3.54 (br s, 4H), 3.69 (t, J=4.4 Hz, 4H), 4.81 (m, 1H) 6.49 (br s, 1H), 7.13-7.18 (m, 1H), 7.29 (d, J=5.2 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 8.34 (s, 1H). Mass Spectrum (ESI) m/e=527.3 (M+1).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH:4]=[CH:3][NH:2]1.S(=O)(=O)(O)O.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>>[N+:12]([C:3]1[NH:2][O:1][CH:6]=[CH:5][CH:4]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: C1=CNOC=C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])C1=CC=CON1

Procedure:
Oxazine XXIV (1.27 mmol) was dissolved in sulfuric acid (10.2 g, 5.57 ml, 102 mmol, Eq: 80). The light yellow solution was cooled in an ethanol/ice bath. Nitric acid fuming (1.78 mmol) was added dropwise over a period of 1 minute. The mixture was stirred under ice-bath cooling for 30 minutes and poured carefully onto ice-water (30 ml). The mixture was basified with a 5N NaOH solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel [Eluent: Heptane/ethyl acetate (0% to 50%)] to afford the pure nitro-oxazine XXV.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:32]=[CH:31][C:11]3[NH:12][C:13]([C:15]4[C:23]5[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=5)[N:17]([CH:25]5[CH2:30][CH2:29][CH2:28][CH2:27][O:26]5)[N:16]=4)=[N:14][C:10]=3[CH:9]=2)[CH2:5][CH2:4][O:3]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56](O)=[O:57]>CN(C=O)C>[F:52][C:53]1([F:59])[CH2:55][CH:54]1[C:56]([NH:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[N:16]=[C:15]2[C:13]1[NH:12][C:11]2[CH:31]=[CH:32][C:8]([N:6]3[CH2:5][CH2:4][O:3][CH:2]([CH3:1])[CH2:7]3)=[CH:9][C:10]=2[N:14]=1)=[O:57]
Reactant: O=C(O)C1CC1(F)F
Reactant: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(N)cc45)nc3c2)CCO1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1CN(c2ccc3[nH]c(-c4nn(C5CCCCO5)c5ccc(NC(=O)C6CC6(F)F)cc45)nc3c2)CCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.8 %

Procedure:
3-(5-(2-Methylmorpholino)-1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (20 mg, 0.046 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (9.37 mg, 0.069 mmol), EDC (13.30 mg, 0.069 mmol) and sodium bicarbonate (3.88 mg, 0.046 mmol) was added to a solution of 2,2-difluorocyclopropanecarboxylic acid (5.64 mg, 0.046 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (16 mg) as a solid. 1H NMR: (400 MHz, CD3OD): δ 8.51 (s, 1H), 7.75-7.65 (m, 2H), 7.56 (m, 1H), 7.04 (m, 2H), 5.84 (dd, 1H, J=2.4 and 9.6 Hz), 3.98 (m, 2H), 3.80 (m, 3H), 3.51 (m, 1H), 3.43 (m, 1H), 2.77 (m, 2H), 2.60 (m, 1H), 2.11 (m, 3H), 1.85 (m, 2H), 1.70 (m, 2H), 1.23 (d, 3H, J=6.0 Hz); ESI-MS [M+H]+: 537.1.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17]>CN1CCCC1=O.C(OCC)(=O)C.P([O-])([O-])([O-])=O>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[N:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[CH:10]=[CH:9][S:8][C:7]=12
Reactant: Cc1cc2ccsc2c(Cl)n1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2nc(C)cc3ccsc23)c(OC)c1
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-5-methyl-thieno[2,3-c]-pyridine (100 mg, 0.544 mmol) and 2,4-dimethoxybenzylamine (0.245 mL, 1.63 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was heated to 180° C. in an oil bath for 19 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and aqueous phosphate buffer (1.0 M, pH 7, 20 mL). The separated organics were sequentially washed with water (10 mL), aqueous phosphate buffer (1.0 M, pH 7, 10 mL), water (10 mL), and brine (10 mL). The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (5-25% ethyl acetate/hexanes, linear gradient) to give N-(2,4-dimethoxybenzyl)-5-methylthieno[2,3-c]pyridin-7-amine. MS ESI calc'd. for C17H19N2O2S [M+H]+ 315. found 315.
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:20])[N:10]([OH:19])[C:11](=[O:18])[C:12]3[C:17]=2[C:16]=1[CH:15]=[CH:14][CH:13]=3>C(O)C>[OH:19][N:10]1[C:9](=[O:20])[C:8]2[CH:7]=[CH:6][C:5]([S:2][CH3:1])=[C:16]3[C:17]=2[C:12](=[CH:13][CH:14]=[CH:15]3)[C:11]1=[O:18]
Reactant: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc2c3c(cccc13)C(=O)N(O)C2=O
Yield: 77.1 %

Procedure:
Sodium thiomethoxide (0.9 g, 12.0 mmol) was added to a solution of 6-bromo-2-hydroxy-benzo[de]isoquinoline-1,3-dione (1.2 g, 4.0 mmol, from Example 4) in ethanol (200 mL). The mixture was refluxed for 48 hours and concentrated. The solid residue was dissolved in water and acidified with concentrated HCl to pH 4. The resulting precipitate was filtered, washed with water, and dried to give 0.8 g of the title compound, mp 301-206° C.
Reaction SMILES: CN(C)C=O.N1C(Cl)=NC(Cl)=NC=1[Cl:8].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([CH:23](O)[CH3:24])=[C:18]([O:26][CH3:27])[C:17]=1[CH:28]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]1>C(Cl)Cl.O>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([CH:23]([Cl:8])[CH3:24])=[C:18]([O:26][CH3:27])[C:17]=1[CH:28]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)Cl)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
N,N-Dimethylformamide (0.92 mL, 12 mmol) was added to solid cyanuric chloride (2.2 g, 12 mmol) at room temperature (DMF is absorbed by the solid). The mixture was allowed to stand for 10 min, treated with methylene chloride (60 mL), and stirred for a few minutes to break up the solid. The reaction mixture was treated with a solution of tert-butyl 3-[2,3-dichloro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate (3.0 g, 8.0 mmol) in methylene chloride (30 mL) and stirred at 35-40° C. for 2 h. The reaction mixture was treated with additional N,N-dimethylformamide (1 mL) and stirred at 35-40° C. for 4 h. The reaction required another treatment of N,N-dimethylformamide (1 mL) with stirring at 35-40° C. overnight to proceed to completion. The reaction mixture was diluted with water and dichloromethane. The organic phase was separated and washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, filtered, and concentrated to a crude residue. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-40%) to give the desired product (2.8 g, 90%). LCMS for C13H15Cl3NO3 ([M-(t-Bu)+H]+H)+: m/z=338.0, 340.0; Found: 337.9, 339.9.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[Cl-:13].[NH4+:14]>CO>[ClH:13].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[NH:14])[NH2:10])=[CH:7][CH:6]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: N#Cc1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N=C(N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.3 %

Procedure:
Sodium methoxide (0.81 g, 15 mmol) was dissolved in methanol (150 mL) and 4-bromobenzonitrile (27.3 g, 150 mmol) was added and the mixture was stirred at 25° C. for 24 h. Solid ammonium chloride (8.1 g, 150 mmol) was added and the mixture was stirred for an additional 24 h. The mixture was filtered, the solid was washed with methanol and ether, and the filtrate was combined and concentrated. The white residue was collected and washed thoroughly with ether and dried under vacuum to give 4-bromobenzenecarboximidamide hydrochloride (16 g, 54%) as a white solid. HRMS: calcd for C7H7BrN2+H+, 198.98654; found (ESI, [M+H]+), 198.9868; Analytical HPLC: purity 98.4% at 246 nm, 3.4 min; 97.8% at 210-370 nm, 3.4 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[C:5]([Cl:19])[N:4]=1.[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][C:32]2[CH:41]=[CH:40][C:35]3[O:36][CH2:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH2:2][C:3]2[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]=[C:5]([Cl:19])[N:4]=2)[CH2:31][C:32]2[CH:41]=[CH:40][C:35]3[O:36][CH2:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:27][CH:28]=1
Reactant: CCCCc1c(CBr)nc(Cl)nc1-c1ccccc1
Reactant: COC(=O)c1ccc(CNCc2ccc3c(c2)OCCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1c(CN(Cc2ccc(C(=O)OC)cc2)Cc2ccc3c(c2)OCCO3)nc(Cl)nc1-c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of impure 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (288 mg) and 4-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (190 mg, 0.606 mmol) in CH3CN containing K2CO3 (300 mg) is stirred at room temperature. The reaction is monitored by TLC until complete consumption of 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (24 hours). The mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the resulting residue is purified by flash chromatography on silica gel. Elution with 5:1 hexanes-EtOAc followed by 4:1 hexanes-EtOAc affords 215 mg of pure 4-{[(5-butyl-2-chloro-6-phenyl pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, J=8.1 Hz, 2H), 7.44-7.33 (m, 7H), 6.84 (s, 1H), 6.79 (s, 2H), 4.22 (s, 4H), 3.90 (s, 3H), 3.74 (s, 2H), 3.72 (s, 2H), 3.55 (s, 2H), 2.64-2.56 (m, 2H), 1.01 (m, 2H), 0.90 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 572 [M+1].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:11][CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[CH:5][CH:4]=1.C(O[CH:21](OCC)[CH2:22][CH2:23][CH2:24][NH:25][CH3:26])C>C(O)C.O>[Cl:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:9]([CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH:21]=[C:22]2[CH2:23][CH2:24][NH:25][CH3:26]
Reactant: CCOC(CCCNC)OCC
Reactant: NN(CCC1CCCC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNCCc1cn(CCC2CCCC2)c2ccc(Cl)cc12
Temperature: 60 °C
Yield: 56.7 %

Procedure:
28% aqueous HCl (0.3 mL, 2.26 mmol) was added to a solution of N-(4-Chloro-phenyl)-N-(2-cyclopentyl-ethyl)-hydrazine (0.54 g, 2.26 mmol) in ethanol (2.5 mL) and water (1 mL) under a nitrogen atmosphere. The reaction was heated to 60° C. (oil bath temperature) and 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated at reflux for 2.5 h. The reaction was cooled to 60° C. and then more 4,4-diethoxy-N-methylbutan-1-amine (0.32 g, 1.84 mmol) was added. The reaction was heated to reflux and then more 28% aqueous HCl (0.15 mL, 1.13 mmol) was added. The reaction was heated to reflux for a further 3.5 h. The reaction was cooled and concentrated under reduced pressure. The red brown residue was subjected to column chromatography (silica gel, eluent: EtOAc followed by EtOAc:EtOH:NH4OH 90:10:1) to give the product (0.318 g, 46%).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:3]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CCO>[CH:7]1([C:4]2[N:3]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][C:20]4[CH:29]=[CH:30][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[CH2:28][CH2:27]3)[S:6][N:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Clc1nc(C2CCCCC2)ns1
Reactant: COc1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(CCN2CCN(c3nc(C4CCCCC4)ns3)CC2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-chloro-3-cyclohexyl-1,2,4-thiadiazole (32.0 mg, 158 μmol), 1-(4-methoxyphenethyl)piperazine dihydrochloride (51.0 mg, 174 μmol) and DIPEA in EtOH was heated for 30 min at an oil bath temperature of 90° C. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 13.7 mg (22%) of the title compound as light brown solid. MS (m/e): 387.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:21][CH:22]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:23]([OH:27])[C:24]([NH2:26])=[O:25].O[NH-].O=[N-]>>[NH2:26][C:24](=[O:25])[C:23](=[O:27])[CH:22]([NH:21][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:1])([F:20])[F:19])[CH:4]=1)=[O:15])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)[C@H]1CCC(=O)N1Cc1cccc(C(F)(F)F)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1cccc(C(F)(F)F)c1

Procedure:
Coupling of (R)-1-(3-trifluoromethyl-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.