Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][CH:31]1[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH:35]([N:33]5[CH2:34][CH:31]([F:30])[CH2:32]5)[CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1CN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.079 g, 0.20 mmol), 3-fluoro-[1,3′]biazetidinyl (0.029 g, 0.22 mmol) in DCE (3 mL), trimethoxymethane (0.22 mL, 2 mmol) and acetic acid (0.012 mL, 0.2 mmol) was stirred for 5 h at room temperature. Sodium triacetoxyborohydride (0.065 g, 0.30 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was partitioned between DCM and water. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 16:84) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 5:95) to give 345 as an off-white solid (0.054 g, 53%). LCMS (Method G): RT=5.78 min, [M+H]+ 506.2. 1H NMR (CDCl3, 400 MHz) δ 8.02-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.28-7.24 (m, 2 H); 5.15 (dt, J=57.3, 5.4 Hz, 1 H); 4.38-4.33 (m, 4 H); 3.90-3.85 (m, 6 H); 3.83 (s, 2 H); 3.72-3.62 (m, 3 H); 3.48-3.39 (m, 3 H); 3.35 (q, J=7.5 Hz, 2 H); 3.35-3.19 (m, 2 H); 3.17-3.15 (m, 2 H); 1.44 (t, J=7.5 Hz, 3 H)
Reaction SMILES: ClC1C=CC=CC=1CCCN1C(=O)C(COS(C)(=O)=O)=CC(C2C=CC3OCCC=3C=2)=N1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]3[CH:43]=[C:44]([C:49]([O:51]C)=[O:50])[C:45](=[O:48])[NH:46][N:47]=3)=[CH:41][C:36]=2[CH2:35][CH2:34]1.CS(O[CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=1)(=O)=O>>[C:49]([C:44]1[C:45](=[O:48])[N:46]([CH2:58][CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[CH:63][CH:62]=2)[N:47]=[C:42]([C:40]2[CH:39]=[CH:38][C:37]3[O:33][CH2:34][CH2:35][C:36]=3[CH:41]=2)[CH:43]=1)([OH:51])=[O:50]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Agent: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccccc2Cl)c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccc(Cl)cc2)c1=O
Yield: 71 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(4-chlorophenyl)-1-propanol methanesulfonate, to thereby yield the title compound as a yellow powder (yield: 71.0%).
Reaction SMILES: F[C:2]1[CH:7]=C[CH:5]=[C:4](F)[C:3]=1[NH:9][C:10]([C:12]1[S:13][C:14](C2C=C(C(F)(F)F)C=CC=2Cl)=[CH:15][CH:16]=1)=[O:11].[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=1.CC1[CH:42]=[N:43]C=CC=1N>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:14]2[S:13][C:12]([C:10](=[O:11])[NH:9][C:3]3[CH:2]=[CH:7][N:43]=[CH:42][C:4]=3[CH3:5])=[CH:16][CH:15]=2)[CH:32]=1
Reactant: Cc1cnccc1N
Reactant: O=C(Nc1c(F)cccc1F)c1ccc(-c2cc(C(F)(F)F)ccc2Cl)s1
Reactant: COC(=O)c1ccc(C)c(I)c1
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)Nc3ccncc3C)s2)c1

Procedure:
Compound 4 was synthesized in an analogous fashion as described for Compound 1 except that 3-iodo-4-methyl-benzoic acid methyl ester was used instead of 1-chloro-2-iodo-4-trifluoromethyl-benzene in step 1, and 3-methyl-4 amino pyridine was used instead of 2,6-difluoroaniline in step 2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1)#[CH:2].[C:20]([O:26][CH2:27][N:28]=[N+:29]=[N-:30])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].N1C(C)=CC=CC=1C>C(O)(C)(C)C.CC#N.[Cu]I>[C:20]([O:26][CH2:27][N:28]1[CH:2]=[C:1]([C:3]2[CH:8]=[C:7]([O:9][C:10]3[C:11]([CH3:19])=[N:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=3)[CH:6]=[CH:5][N:4]=2)[N:30]=[N:29]1)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)OCN=[N+]=[N-]
Reactant: C#Cc1cc(Oc2ccc([N+](=O)[O-])nc2C)ccn1
Agent: [Cu]I
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Solvent: CC(C)(C)O
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cn(COC(=O)C(C)(C)C)nn2)c1
Yield: 83.9 %

Procedure:
A solution of 3-((2-ethynylpyridin-4-yl)oxy)-2-methyl-6-nitropyridine (0.2 g, 0.78 mmol) and azidomethyl pivalate (0.209 g, 1.33 mmol; See: Syn Lett. 2005, (18), 2847-2850) were combined in tert-butanol (3 mL) and treated with copper(I) iodide (0.030 g, 0.157 mmol) followed by a solution of 2,6-lutidine (0.091 mL, 0.78 mmol) in MeCN (3 mL) and the resultant mixture was stirred at RT for 3 h. The mixture was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc and the combined organics were washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by silica gel chromatography (EtOAc/Hex) to afford (4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)-1H-1,2,3-triazol-1-yl)methyl pivalate (0.27 g, 84%) as an orange foam. 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.60 (d, J=5.7 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.12 (dd, J=5.6, 2.5 Hz, 1H), 6.37 (s, 2H), 2.50 (s, 3H), 1.11 (s, 9H); MS (ESI) m/z: 413.2 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19].CCN(CC)CC.C[O:29][C:30](=O)[C:31]1[C:36]([NH:37][C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:43]Br>CN(C=O)C>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:16]2[C:30](=[O:29])[C:31]3[C:32](=[CH:33][CH:34]=[CH:35][C:36]=3[NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[CH2:43]2)[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][C:5]=1[O:17][CH2:18][CH3:19]
Reactant: COC(=O)c1c(CBr)cccc1NC(=O)C1CC1
Reactant: CCOc1cc(C(N)CS(C)(=O)=O)ccc1OC(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Temperature: 90 °C
Yield: 25.5 %

Procedure:
To the DMF solution (20 ml) of 1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethylamine (0.80 g, 2.7 mmol) was added Et3N (1.6 ml, 12 mmol) followed by 2-bromomethyl-6-(cyclopropanecarbonyl-amino)-benzoic acid methyl ester (1.0 g, 3.2 mmol). The mixture was heated at 90° C. for 12 hours then cooled to room temperature. The mixture was extracted with EtOAc (50 ml) and water (50 ml). The organic layer was washed with water (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated in vacuo. The resulted oil was purified by silica gel chromatography to give cyclopropanecarboxylic acid {2-[1-(4-difluoromethoxy-3-ethoxy-phenyl)-2-methanesulfonyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.35 g, 30%): mp 115-117° C.; 1H NMR (CDCl3) δ 0.83-0.92 (m, 2H, c-CH2), 1.09-1.13 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, CH3), 1.66-1.70 (m, 1H, c-CH), 2.98 (s, 3H, SO2CH3), 3.64 (dd, J=3.8, 14 Hz, 1H, CH2), 4.10 (q, J=6.8 Hz, 2H, OCH2), 4.33 (dd, J=10, 14 Hz, 1H, CH2), 4.37 (dd, J=5, 50 Hz, 2H, CH2N), 5.69-5.74 (m, 1H, NCH), 6.57 (t, JH-F=75 Hz, 1H, CF2H), 6.94-7.04 (m, 3H, Ar), 7.18 (d, J=7.5 Hz, 1H, Ar), 7.47 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8.5 Hz, 1H, Ar), 10.42 (s, 1H, NH); 13C NMR (CDCl3) δ 9.06, 15.3, 16.9, 42.4, 49.0, 52.5, 56.3, 65.6, 112.4, 113.9, 116.6, 117.5, 117.6, 118.7, 119.9, 120.7, 123.8, 134.5, 136.5, 138.9, 141.1, 141.9, 151.9, 170.9, 173.4; Anal Calcd for C24H26F2N2O6S: C, 56.68; H, 5.15; N. 5.51. Found: C, 56.72; H, 5.15; N. 5.38.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:8]=[C:7]([Br:16])[CH:6]=1)[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[CH:8]=[C:7]([Br:16])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Br)cc(SCC(C)=O)c1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cc(Br)cc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 3-Bromo-5-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][C:17]=2[Br:18])[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[CH2:19]([N:21]1[C:25]([NH:26][C:27]2[C:28](=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=2)[C:29](O)=O)=[CH:24][CH:23]=[N:22]1)[CH3:20].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:41]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:41])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[CH:16][C:17]=3[Br:18])[CH3:2].[CH2:19]([N:21]1[C:25]2=[N:26][C:27]3[C:28]([C:29]([Cl:41])=[C:24]2[CH:23]=[N:22]1)=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=3)[CH3:20]
Reactant: CCn1nccc1Nc1ccc(Br)cc1C(=O)O
Reactant: CCn1nccc1Nc1c(Br)cccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Product: CCn1ncc2c(Cl)c3cccc(Br)c3nc21
Temperature: 25 °C
Yield: 64 %

Procedure:
and (c) A mixture of N-(1-ethylpyrazol-5-yl)-3-bromoanthranilic acid and N-(1-ethylpyrazol-5-yl)-5-bromoanthranilic acid (34.8 g, 0.11 mol) and POCl3 (100 ml) is heated at reflux for 8 hours. The reaction mixture is cooled to room temperature, and then is poured into ice water and neutralized with concentrated NH4OH. The mixture is extracted with CH2Cl2 and the CH2Cl2 layer is dried over MgSO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 2.7 g of 1-ethyl-4-chloro-8-bromo-1H-pyrazolo[3,4-b]quinoline (labelled as Example 44(b)) and 22.5 g (64%) of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline (labelled as Example 44(c)).
Reaction SMILES: Cl.[C:2]([NH:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])=[CH:21][CH:20]=3)=[C:15]([F:43])[CH:14]=2)[CH2:8]1)(=[O:4])[CH3:3]>O1CCOCC1.ClCCl.O>[C:2]([NH:5][CH2:6][C@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])=[CH:23][CH:24]=3)=[C:15]([F:43])[CH:14]=2)[CH2:8]1)(=[O:4])[CH3:3]
Reactant: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@@H]1CN(c2ccc(-c3ccc(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc3)c(F)c2)C(=O)O1

Procedure:
HCl (4.0 M in 1,4-dioxane, 1.0 mL) was added to a solution of (2R)-4-{4′-[(5R)-5-(acetamidomethyl)-2-oxo-1,3-oxazolidin-3-yl]-2′-fluorobiphenyl-4-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (50 mg, 0.083 mmol) in 1,4 dioxane/dichloromethane/water (1:1:1, 3 mL). After 15 minutes reaction was concentrated to give a white solid. The solid was triturated with a mixture of diethyl ether/2-propanol (10:1, 10 mL) for 2 hours. The title compound was collected as a white solid (16 mg, 37%) by filtration. LCMS m/z 522.6 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 1.84 (s, 3H) 1.88-1.98 (m, 1H) 2.37-2.48 (m, 1H) 2.63-2.76 (m, 2H) 3.05 (s, 3H) 3.43 (t, J=5.47 Hz, 2H) 3.78 (dd, J=9.28, 6.35 Hz, 1H) 4.17 (t, J=8.98 Hz, 1H) 4.70-4.82 (m, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.40 (dd, J=8.49, 2.25 Hz, 1H) 7.45-7.51 (m, 2H) 7.51-7.62 (m, 2H) 8.26 (t, J=5.86 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:32][C:33]1[CH:34]=[N+:35]([O-:58])[CH:36]=[C:37]([Cl:57])[C:38]=1[CH2:39][C@@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:51])[F:50])=[C:44]([O:52][CH2:53][CH:54]2[CH2:56][CH2:55]2)[CH:43]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([S:18][CH2:19][C:20]([O:22][C@H:40]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH:49]([F:50])[F:51])=[C:44]([O:52][CH2:53][CH:54]2[CH2:55][CH2:56]2)[CH:43]=1)[CH2:39][C:38]1[C:37]([Cl:57])=[CH:36][N+:35]([O-:58])=[CH:34][C:33]=1[Cl:32])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
To a solution of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetic acid (0.206 g, 0.491 mmol) in dry DCM (16 ml), EDC (0.157 g, 0.818 mmol) and DMAP (0.050 g, 0.409 mmol) were added followed by (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.172 g, 0.409 mmol), and the resulting solution was stirred overnight at RT. Additional EDC (0.080 g, 0.42 mmol) and DMAP (0.025 g, 0.20 mmol) were added, and the reaction was stirred at the same temperature for 24 hours. The mixture was partitioned between DCM and HCl 1N; the organic phase was washed with aqueous NaHCO3 and dried over Na2SO4. The solvent was removed and the crude was purified by preparative HPLC affording (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoylthio)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.082 g, 0.100 mmol, 24.4% yield, MS/ESI+ 821.1 [MH]+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[S:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=O)[CH2:25][CH2:24]1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH:26]4[C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[S:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=C1CCSc2ccccc21
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NC4CCSc5ccccc54)cccc3n2)o1

Procedure:
The title compound, MS: m/e=402.5 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and thiochroman-4-one as described in example 26.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([OH:21])=[O:20])[CH:8]=2)[CH3:2].[CH2:22]([N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][Cl:30])[CH2:23][CH2:24][CH3:25]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[ClH:30].[ClH:30].[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([O:18][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])[CH:8]=2)[CH3:2]
Reactant: CCCCN(CCCC)CCCCl
Reactant: CCn1c2ccc(C(=O)O)cc2c2cc(C(=O)O)ccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCN(CCCC)CCCOC(=O)c1ccc2c(c1)c1cc(C(=O)OCCCN(CCCC)CCCC)ccc1n2CC
Product: Cl

Procedure:
By the procedure of Example 2, one equivalent of 9-ethylcarbazole-3,6-dicarboxylic acid is allowed to react with two equivalents of 3-dibutylaminopropylchloride in the presence of a catalytic amount of benzyltrimethylammonium chloride to give the product.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16](=[C:20]([Cl:22])[Cl:21])[C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:5]([C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:6][C:17]([C:16]([Cl:15])=[C:20]([Cl:22])[Cl:21])=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(Cl)C(Cl)=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)C(Cl)=C(Cl)Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-t-butyl-1-benzoylhydrazine (1.5 g, 0.008 M) in methylene chloride at 5° C. was added, simultaneously and separately, trichloroacryloylchloride (1.7 g, 0.009 M) and triethylamine (0.9 g, 0.009 M). After addition, the reaction was warmed to room temperature and stirred for 3 h. The flask's contents were diluted with 50 ml methylene chloride and washed with water (3×75 ml) and brine solution (1×75 ml). The organic layer was dried over magnesium sulfate and the solvent removed under vacuum to afford N'-t-butyl-N-(1,2,2-trichlorovinyl)carbonyl-N'-benzoylhydrazine as a white solid product.
Reaction SMILES: [Cl-].[CH3:2][NH3+].[C:4]1([CH:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[C:12]([NH2:26])[O:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN.Cl>O.CO>[C:4]1([CH:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)=[C:12]([NH:26][CH3:2])[O:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: C[NH3+]
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
In this example, 2 g of methylammonium chloride was added at room temperature to a stirred slurry containing 10 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 60 ml of aqueous 40 wt % methyl amine followed by the addition of 50 ml of methanol. The resulting suspension was heated to reflux and refluxed overnight (about 15--18 hours). The mixture was cooled to room temperature and added to a dilute acid solution containing 58 ml of aqueous 12N hydrochloric acid in 300 ml of water. This mixture was extracted twice with methylene chloride. The methylene chloride extracts were combined and successively washed once with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and evaporated under vacuum affording 9.2 g of the title compound as a pale yellow foam (yield=88%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:3]=1.Cl.[F:25][C:26]([F:31])([F:30])[C@@H:27]([NH2:29])[CH3:28].C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[N:5]=[C:6]([NH:29][C@@H:27]([CH3:28])[C:26]([F:31])([F:30])[F:25])[C:7]=1[C:8]1[C:9]([F:16])=[CH:10][C:11]([F:15])=[CH:12][C:13]=1[F:14]
Reactant: C[C@H](N)C(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Cl)nc(-c3cnccn3)nc2Cl)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1nc(-c2cnccn2)nc(Cl)c1-c1c(F)cc(F)cc1F)C(F)(F)F
Temperature: 90 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
A mixture of 4,6-dichloro-2-pyrazin-2-yl-5-(2,4,6-trifluorophenyl)pyrimidine (205 mg, 0.57 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (298 mg, 2 mmol), and N,N-diisopropylethylamine (258 mg, 2 mmol) in 5 mL of N,N-dimethylformamide is stirred at 90° C. in a sealed tube for 18 h. The reaction mixture is partitioned between ethyl acetate and saturated sodium chloride. The organic layer is washed with saturated sodium chloride (×3), dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 20% ethyl acetate in hexanes to 50% ethyl acetate in hexanes. Concentration provides 6-chloro-2-pyrazin-2-yl-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-5-(2,4,6-trifluorophenyl)pyrimidin-4-amine as a light yellow solid (111 mg). MS: m/z 434.1 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[OH:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12](OC)=[O:13])=[CH:8][CH:7]=1>CO>[CH2:1]([NH:4][C:12](=[O:13])[CH2:11][O:10][C:9]1[CH:16]=[CH:17][C:6]([OH:5])=[CH:7][CH:8]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: COC(=O)COc1ccc(O)cc1
Solvent: CO
Product: CCCNC(=O)COc1ccc(O)cc1
Reaction time: 72 h

Procedure:
A solution of 1-propylamine (4.1 ml) and methyl 4-hydroxyphenoxyacetate (3.64 g) in methanol (50 ml) was left to stand for 72 hours at ambient temperature. The solvent was evaporated in vacuo and the residue taken up in ethyl acetate. The solution was washed sequentially with 1M HCl (2×25 ml) and brine (30 ml), dried (MgSO4) and the solvent evaporated to give N-(1-propyl)-4-hydroxyphenoxyacetamide as a red oil, NMR: 0.95(t, 3H, CH3 ), 1.55(m, 2H, CH2), 3.3(q, 2H, CH2N), 4.4(s, 2H, CH2O), 6.5-6.7(broad s, 1H, OH), 6.8(s, 4H, phenyl-H); m/e 227 (M+NH4)+, 210(M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH2:2][CH2:3][CH3:4].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:32]([O:31][C:29](=[O:30])[C:28]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:7]=1)([CH3:35])[CH3:34])[CH3:33]
Reactant: CCCCc1ccc(O)cc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCc1ccc(OC(C)(C)C(=O)OCC)cc1OCCc1nc(-c2ccccc2)oc1C
Temperature: 55 °C
Yield: 82.3 %

Procedure:
A mixture of 4-butyl-3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenol (0.11 g, 0.313 mmol), ethyl bromoisobutyrate (0.18 mL, 1.25 mmol) and cesium carbonate (0.41 g, 1.25 mmol) in anhydrous DMF (2 mL) was heated for 18 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 5-15% EtOAc/Hex to give a yellow oil (0.12 g, 68%). 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J=7.6, 1.7 Hz, 2H), 7.45-7.39 (m, 3H), 6.90 (d, J=7.8 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 6.29 (dd, J=8.3, 2.0 Hz, 1H), 4.25-4.17 (m, 4H), 2.97 (t, J=6.4 Hz, 2H), 2.47 (t, J=7.6 Hz, 2H), 2.37 (s, 3H), 1.56 (s, 6H), 1.43 (quintet, J=7.7 Hz, 2H), 1.30-1.22 (m, 5H), 0.86 (t, J=7.3 Hz, 3H), MS (ES) m/e 466 (M+1).