Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH3:24])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc(CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nc(CN2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C

Procedure:
To a mixture of 5-chloro-4-(4-((2-methylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.06 g, 0.19 mmol, 1 eq), EtOH (3.3 mL), and DMF (0.44 mL), 4-(morpholinomethyl)-benzaldehyde (0.043 g, 0.21 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.57 mL, 0.57 mmol). The reaction mixture was heated at 85° C. for 24 h, allowed to cool to room temperature, and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.018 g, 18%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.42 (m, 4H), 2.63-2.70 (m, 7H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.8 Hz, 4H), 3.64 (s, 2H, NCH2), 3.68-3.74 (m, 4H), 7.32 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.10 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 13.43 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.25 min—524/526 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 524.1999, calculated for C26H31ClN7OS (M+H)+: 524.1999;
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[CH2:23]([O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[N:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)cc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 100 g of dimethyl 4-hydroxypyridine-2,6-dicarboxylate hydrochloride disloved in 500 ml of N,N-dimethylformamide, 122 g of potassium carbonate was added, and the mixture was stirred at room temperature for 1 hour. 52.5 ml of benzyl bromide was added to the resulting reaction mixture, and it was stirred at 50° C. overnight. The reaction mixture was poured into water; and then the resulting white solid was collected after filtration, washed with water, and dried in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[F:45][C:42]1[CH:43]=[CH:44][C:39](/[C:37](/[CH3:38])=[CH:36]/[N:6]2[C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]2=3)=[CH:40][CH:41]=1
Reactant: CC(=CBr)c1ccc(F)cc1
Reactant: CN1CCc2[nH]c3cc(C(F)(F)F)ccc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3ccc(C(F)(F)F)cc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.78 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (14 mg, 0.078 mmol), L-proline (17 mg, 0.156 mmol) and potassium phosphate (330 mg, 1.56 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (200 mg, 0.94 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 85° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 25 mg. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 7.80 (m, 2H), 7.76 (d, 1H), 7.60 (s, 1H), 7.42 (d, 1H), 7.30 (t, 2H), 7.20 (s, 1H), 4.35 (m, 2H), 3.05 (s, 3H), 2.90 (m, 4H), 1.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH:10]([C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([CH3:13])=[CH:3][C:2]=1[OH:1])([CH3:12])[CH3:11]
Reactant: C1CCNC1
Reactant: Cc1cc(O)c(C(C)C)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c(C(C)C)cc1CN1CCCC1
Yield: 76.5 %

Procedure:
4-Hydroxy-5-isopropyl-2-methyl-benzaldehyde (1.0 g, 5.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.58 mL, 7 mmol) and NaB(OAc)3H (1.49 g, 7 mmol) in CH2Cl2 (10 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (25 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×25 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (1.0 g, 80%) was obtained as dark-yellow crystals. LCMS-data: (M+H)+ 234.1 and 235.1 (calculated for C15H23NO 233.4). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.90 (s, 1H, Ar—H), 6.54 (s, 1H, Ar—H); 3.40 (s, 2H, ArCH2), 3.13 (m, 1H, CH(CH3)2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 2.17 (s, 3H, CH3), 1.60-1.70 (m, 4H, CH2CH2CH2CH2), 1.12 (d, 6H, J=6.9 Hz, CH(CH3)2).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([N:14]([C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)cc(Cl)n1
Solvent: O
Solvent: CC#N
Product: CCCCN(CC)c1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:37][CH3:38])=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[CH2:35][NH2:36])[CH:24]=1)([CH3:18])[CH3:17].[BH3-]C#N.[Na+].O>CO.C(O)(=O)C>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([O:37][CH3:38])=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[CH2:35][NH:36][CH2:7][C:6]2[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:24]=1)([CH3:18])[CH3:17]
Reactant: O=Cc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-nitro-5-(trifluoromethyl)benzaldehyde (366 mg, 1.67 mmol) in MeOH (4 mL) was added a solution of 1-[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanamine (270 mg, 0.84 mmol) in MeOH (4 mL) followed by addition of NaCNBH3 (105 mg, 1.67 mmol) and one drop of acetic acid. The reaction was stirred for 24 hours at room temperature and then poured into H2O (30 mL). The mixture was extracted with EtOAc (60 mL), and the organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 25% EtOAc/hexanes afforded {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-nitro-5-(trifluoromethyl)benzyl]amine as a yellow oil. Rf=0.45 (15% EtOAc/hexanes). LCMS=527.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.74 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.5 Hz, 2.0 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.70 (s, 3H), 2.87 (m, 1H), 1.25 (d, J=7.0 Hz, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH:14](N(CC)C(C)C)(C)C.CI>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([O:11][CH3:14])=[O:10])=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)COc1ccc(CO)cc1
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CO)cc1
Reaction time: 3 h

Procedure:
18.2 g of 4-hydroxymethylphenoxyacetic acid are dissolved together with 17.1 ml of N,N-diisopropylethylamine in 50 ml of DMF, and then 6.1 ml of methyl iodide are added to the stirred solution. The mixture warms slightly during this. The reaction is complete after 3 h. The solvent is removed in vacuo. The residue is taken up in ether, and the solution is extracted once with 0.5 N hydrochloric acid. The aqueous phase is then extracted three times with ether, and the combined ether phases are washed with aqueous sodium bicarbonate solution and concentrated. The residue is dissolved in ethyl acetate and filtered through a short silica gel column. The pale yellowish oil which is obtained after concentration crystallizes on being left to stand.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:14]=[CH:15][C:16]2[C:21]([NH:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=3[S:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:26](Cl)=[O:27])=[N:20][CH:19]=[N:18][C:17]=2[N:41]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([S:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=3)=[C:23]([NH:22][C:21]3[C:16]4[CH:15]=[CH:14][C:13]([CH:10]([CH3:11])[CH3:12])=[N:41][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:24]=2)[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)c(O)c3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Reaction time: 18 h
Yield: 60.2 %

Procedure:
A solution of 5-amino-o-cresol (20.4 mg, 0.1655 mmol) and the product from Example 137B (70mg, 0.1655 mmol) in dichloromethane (4 mL) was treated with triethylamine (0.025 mL, 0.1806 mmol) at room temperature. The resulting solution was stirred for 18 hours. The reaction mixture was then washed with water and brine, and the combined organic layers were dried over MgSO4, the concentrated under vacuum to give a residue which was purified by silica gel chromatography using methanol and dichloromethane as eluent to provide the title compound (55 mg, 65%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6H), 2.07 (s, 3H), 3.17-3.28 (m, 1H), 3.77 (s, 3H), 6.86-7.10 (m, 5H), 7.30-7.46 (m, 3H), 7.64 (d, J=7.35 Hz, 1H), 7.72-7.86 (m, 1H), 7.95 (s, 1H), 8.43-8.68 (m, 1H), 8.77-8.97 (m, 1H), 9.27-9.46 (m, 1H), 10.02 (s, 1H), 10.21-10.40 (m, 1H); MS (APCI) m/z 552 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:9]12([C:5]3[CH:4]=[C:3]([Br:8])[CH:2]=[CH:1][C:6]=3[OH:7])[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34.6 g (200 mmol) of p-bromophenol and 30.4 g (200 mmol) of 1-adamantanol are dissolved in 100 ml of dichloromethane. To the resulting solution there are slowly added 10 ml of concentrated sulfuric acid. The mixture is stirred for 8 hours at ambient temperature, poured into water, neutralized with sodium bicarbonate, extracted with methylene chloride, dried and evaporated. After recrystallization in isooctane 52.8 g of the expected product are obtained. Yield - 86%. Melting point: 140°-141° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Br:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCc1[nH]c(C(=O)O)nc1Br
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Br
Yield: 92 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (0.39 g, 1.67 mmol), 4-bromo-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (25b) (0.18 g, 0.82 mmol), WSC hydrochloride (0.49 g, 2.53 mmol) and HOBT (0.11 g, 0.84 mmol), to obtain 0.33 g of the title compound as a white solid (92%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[NH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C>CN(C=O)C.[Cu]I.O>[C:14]([C:13]([NH:12][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)([CH3:18])[CH3:17])([OH:16])=[O:15]
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Nc1ccc(C(=O)O)c(F)c1)C(=O)O
Temperature: 90 °C
Reaction time: 14 h
Yield: 72.7 %

Procedure:
4-Bromo-2-fluorobenzoic acid (20 g, 91.3 mmol), 2-aminoisobutyric acid (14.5 g, 140 mmol), CuI (3.47 g, 18.22 mmol) and K2CO3 (31.56 g, 227.91 mmol) were mixed in DMF (200 mL), H2O (20 mL) and TEA (0.63 mL, 4.54 mmol). To the reaction mixture was then added 2-acetyl cyclohexanone (2.4 g, 17.1 mmol). The reaction mixture was stirred at 90° C. for 14 h. After completion of the reaction water was added. Aqueous layer was washed with ethyl acetate. Aqueous layer was made acidic by adding 1M citric acid solution (pH˜4). The product was extracted with ethyl acetate (3×200 mL). Combined organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 16 g of 4-(2-carboxypropan-2-ylamino)-2-fluorobenzoic acid as crude product. This crude material was used as such for the next example.
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](\[CH3:11])/[C:6]([O:8]CC)=[O:7].Cl[CH2:13][C:14]1[CH:33]=[CH:32][C:17]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:16][CH:15]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:17]1[CH:32]=[CH:33][C:14]([CH2:13][O:3]/[N:4]=[C:5](\[CH3:11])/[C:6]([OH:8])=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)/C(C)=N/O
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: C/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reaction time: 1 h
Yield: 70 %

Procedure:
Sodium hydride (60% in oil, 127 mg) was added under a nitrogen atmosphere to a solution of ethyl E-2-hydroxyiminopropionate (418 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:3, v/v). This oil was dissolved in tetrahydrofuran (10 ml)-methanol (5 ml), and 1N aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at room temperature for 1 hour. 1N HCl (5.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-isopropylether to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]propionic acid (849 mg, yield 70%) as colorless crystals. m.p. 147-148° C.
Reaction SMILES: [C:1]([CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:4])#[N:2].N[CH2:16][CH2:17][OH:18]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:4][CH:3]([C:1]1[O:18][CH2:17][CH2:16][N:2]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC(C)C#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCC(C)C1=NCCO1

Procedure:
100 mmoles of 2-cyanododecane is treated with 120 mmoles of 2-aminoethanol in 50 ml of 1-butanol in presence of 2.5 mmoles of cadmium acetate dihydrate as outlined under Example 1 to give 2-(2-dodecyl)-2-oxazoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:10]2(=[O:23])=[O:22])=[C:4]([F:24])[CH:3]=1.[N:25]1([C:31](=[O:33])[CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[S:10]3(=[O:23])=[O:22])=[C:4]([F:24])[CH:3]=2)[CH2:27][CH2:26]1)(=[O:33])[CH3:32]
Reactant: O=S1(=O)N(Cc2ccc(Br)cc2F)CCCCN1c1ccccc1
Reactant: CC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(CN3CCCCN(c4ccccc4)S3(=O)=O)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
A mixture of 2-[(4-bromo-2-fluorophenyl)methyl]-7-phenyl-1λ6,2,7-thiadiazepane-1,1-dione (200 mg, 0.48 mmol), 1-(piperazin-1-yl)ethanone (93 mg, 0.72 mmol), Pd2(dba)3 (44 mg, 0.048 mmol), Xant-phos (55 mg, 0.096 mmol), and Cs2CO3 (469 mg, 1.44 mmol) in 1,4-dioxane (10 mL) under nitrogen atmosphere was stirred at 100° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford 2-{[4-(4-Acetylpiperazin-1-yl)-2-fluorophenyl]methyl}-7-phenyl-1λ6,2,7-thiadiaze-pane-1,1-dione as brown oil (68 mg, 31%). 1H NMR (500 MHz, CDCl3) δ ppm 7.35-7.40 (m, 6H), 6.67-6.69 (m, 1H), 6.55-6.58 (m, 1H), 4.50 (s, 2H), 3.76 (t, J=5.5, 2H), 3.60-3.65 (m, 4H), 3.36 (t, J=5.5, 2H), 3.16-3.21 (m, 4H), 2.14 (s, 3H), 1.98 (t, J=5, 2H), 1.90 (t, J=3.5, 2H); LCMS (ESI): m/z=234.9 [M-2-phenyl-1λ6,2,7-thiadiazepane-1,1-dione+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:39])[N:20]([CH:36]([CH3:38])[CH3:37])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29](=[O:35])[O:30][C:31](C)([CH3:33])[CH3:32])[CH:22]=3)=[C:4]([CH3:40])[CH:3]=1.Cl.O1CCOCC1.ClC(OC(C)=C)=O>CO.O.N1C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:6][C:5]([C:18]2[C:19](=[O:39])[N:20]([CH:36]([CH3:38])[CH3:37])[C:21]3[C:26]([CH:27]=2)=[CH:25][N:24]=[C:23]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])=[CH2:32])[CH:22]=3)=[C:4]([CH3:40])[CH:3]=1
Reactant: Cc1cc(F)c(NC(=O)Nc2ccccc2)cc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2n(C(C)C)c1=O
Agent: C=C(C)OC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: C=C(C)OC(=O)Nc1cc2c(cn1)cc(-c1cc(NC(=O)Nc3ccccc3)c(F)cc1C)c(=O)n2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A solution of tert-butyl (3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (0.2 g, 0.367 mmol) in MeOH (3 mL) was treated with HCl in dioxane (4 M, 0.916 mL, 3.67 mmol) and stirred at RT for 16 h. The mixture was concentrated to dryness, treated with pyridine (3 mL) and isopropenyl chloroformate (0.066 g, 0.550 mmol) and stirred at RT for 1 h. Water was added, the mixture stirred for several minutes, extracted with 20% THF/EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with 30% EtOAc/Hex, sonicated and the resulting solid collected via filtration to afford prop-1-en-2-yl (3-(4-fluoro-2-methyl-5-(3-phenylureido)phenyl)-1-isopropyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)carbamate (175 mg, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 9.02 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.15 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.85 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.25 (t, J=7.8 Hz, 2H), 7.15 (d, J=12.2 Hz, 1H), 6.95 (t, J=7.3 Hz, 1H), 5.33 (m, 1H), 4.81 (s, 1H), 4.77 (s, 1H), 2.07 (s, 3H), 1.96 (s, 3H), 1.56 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 530.2 [M+H]+.
Reaction SMILES: [Na].[C:2]([O:12]CC)(=[O:11])[CH2:3][C:4]([C:6]([O:8]CC)=O)=O.[OH-].[Na+].Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:27])[NH2:26])=[CH:21][CH:20]=1.Cl>O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:27][C:6](=[O:8])[CH:4]=[C:3]([C:2]([OH:12])=[O:11])[N:26]=2)=[CH:21][CH:20]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: O=C(O)c1cc(=O)[nH]c(-c2ccc(Cl)cc2)n1
Temperature: 70 °C
Yield: 45 %

Procedure:
To a mixture of diethyl oxalacetate sodium salt (123.2 g, 586 mmol) in water (750 mL) was slowly added aqueous sodium hydroxide (50%, 47 g, 586 mmol). After 1 h the solids had dissolved. 4-Chlorobenzenecarboximidamide monohydrochloride (111.95 g, 586 mmol) was then added, and the mixture was heated at 70° C. overnight. After cooling to room temperature concentrated hydrochloric acid was slowly added (causing foaming) until the pH was lowered to 1.5. The solid was isolated by filtration and washed with water and methanol. The solid was then triturated twice with hot methanol, washed repeatedly with 1 N hydrochloric acid, then once with methanol and dried to afford the title compound (66.07 g).