Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20](O)=[O:21])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[NH:28][NH2:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][CH2:10][C@@H:11]([C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH:29][NH:28][C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:21])[C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NNC(=O)OCc1ccccc1)[C@H](CNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A solution of 1.9 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-4-methylvaleric acid in 3 ml of dry dimethylformamide was cooled to 0° C. under a nitrogen atmosphere and treated with 2.61 g of benzyl carbazate and 1.20 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was allowed to warm to room temperature and then stirred overnight. The mixture was diluted with ethyl acetate and washed in sequence with water, 2M aqueous hydrogen chloride, water, 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulphate and evaporation gave 2.68 g of 2(R)-[2-benzamido-1(R)-(tert-butoxycarbonyl)ethyl]-2′-benzyloxycarbonyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](Br)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)[C:5]3[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=3[CH:16]=2)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5,7-dibromo-benzothiazol-2-yl)-3-ethyl-urea (1.60 g, 0.40 mmol) in DMF-H2O (2:1, 48 mL) was added pyridine-3-boronic acid (0.51 g, 0.42 mmol) and K3PO4 (0.90 g, 0.42 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for 30 min followed by addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (0.35 g, 0.042 mmol). The reaction mixture was then again degassed for 30 min and heated at 120° C. for 1 h under nitrogen atmosphere. DMF was distilled off, water was added into reaction mixture and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified over silica (230-400 M) using ethyl acetate/hexane (gradient) to provide the desired compounds.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:25])[C:12]2[CH:13]=[C:14]([CH2:23]C)[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+].[CH2:29](O)C>>[CH2:25]([N:11]([C:12]1[CH:13]=[C:14]([CH3:23])[C:15]2[O:19][CH2:18][C:17]([CH3:20])([CH3:21])[C:16]=2[CH:22]=1)[C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:26])=[CH:10][CH:9]=1)[CH3:29]
Reactant: CCO
Reactant: CCOC(=O)c1ccc(N(C)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCN(c1ccc(C(=O)O)cc1)c1cc(C)c2c(c1)C(C)(C)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 4-[methyl-(7-ethyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 21, 0.095 g, 0.27 mmol) in 10 mL of ethanol was treated with 2 mL (10 mmol) of 5M sodium hydroxide solution and the reaction mixture was stirred overnight at room temperature, and at 55° C. for 2 hours. The volatiles were removed by distillation in vacuo and the residue was neutralized with dilute hydrochloric acid, and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (0.070 g, 80%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.92 (d, 2H, J=9.0 Hz), 6.83 (d, 1H, J=2.1 Hz), 6.80 (d, 1H, J=2.1 Hz), 6.65 (d, 2H, J=9.0 Hz), 4.30 (s, 2H), 3.34 (s, 3H), 2.64 (q, 2H, J=7.6 Hz), 1.35(s, 6H), 1.23 (t, 3H, J=7.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:37]>C(Cl)Cl.O1CCOCC1>[ClH:37].[ClH:37].[ClH:37].[Br:1][C:2]1[CH:3]=[C:4]2[C:10](/[CH:11]=[C:12]3\[O:13][C:14]4[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[C:20]([OH:36])[CH:19]=[CH:18][C:15]=4[C:16]\3=[O:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncc(Br)cc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ncc(Br)cc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.018 g, 0.032 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one trihydrochloride (0.014 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].N1CCCCC1>N1C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(F)c(C=O)c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(F)c(/C=C/C(=O)O)c1
Yield: 95.8 %

Procedure:
A solution of 2-fluoro-5-methoxybenzaldehyde (10.00 g, 64.9 mmol), malonic acid (13.4 g, 128.8 mmol), piperidine (2.00 mL) and pyridine (100 mL) was heated to 110° C. for 2 h. After this time the solvent was removed in vacuo and the residue taken up in ethyl acetate and washed with aqueous hydrochloric acid (2N, 100 mL). The organic solvent was dried (MgSO4) and the solvent evaporated in vacuo. The solid was recrystallised from hot etahanol to give a white solid (12.2 g, 95%); δH (300 MHz, DMSO) 7.60 (1H, d, J 7 Hz, CH═C), 7.31-7.28 (1H, m, Ar), 7.20 (1H, t, Ar), 7.07-6.97 (1H, m, Ar), 6.62 (1H, d, J 8 Hz, CH═CH), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH3:1][C@:2]12[C:9]3[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=3[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3]2.[C:17]([OH:26])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].[CH2:27]([OH:29])[CH3:28]>[OH-].[Na+].CCOCC>[OH2:14].[C:17]([O:26][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][C:12]=1[CH:27]=[O:29])[N:7]([CH3:15])[C@H:6]1[N:5]([CH3:16])[CH2:4][CH2:3][C@@:2]21[CH3:1])(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].[CH:27]([C:28]1[CH:13]=[C:8]2[C:9]([C@:2]3([CH3:1])[CH2:3][CH2:4][N:5]([CH3:16])[C@@H:6]3[N:7]2[CH3:15])=[CH:10][C:11]=1[O:25][C:17](=[O:26])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20])=[O:29]
Reactant: O=C(O)c1ccccc1O
Reactant: CCO
Reactant: CN1CC[C@@]2(C)c3cc(O)ccc3N(C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CN1CC[C@@]2(C)c3cc(OC(=O)c4ccccc4O)c(C=O)cc3N(C)[C@@H]12
Product: O
Temperature: 45 °C

Procedure:
A solution prepared from 6-formyl-N,N-diethylcarbamate ester of eseroline (960 mg) in ethanol (20 ml) and 10% NaOH (10 ml) was degassed and heated at 45° C. for 30 minutes. The solution was poured into degassed sodium bicarbonate solution (15 ml) and extracted with ethyl acetate (3×150 ml). The ethyl acetate solution was washed with brine (150 ml), dried over MgSO4, and concentrated to an oil. Purification was effected by flash chromatography over silica gel using 1% CH3OH/DCM. The pure product thus obtained weighed 722 mg as an oil. The oil was dissolved in ether (15 ml) and treated with a solution of salicylic acid (405 mg) in ether (20 ml). The crystalline product weighed 1.04 g, mp 156°-157° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[CH:20]=[CH:19][S:18][CH:17]=3)([C:11]3[CH:15]=[CH:14][S:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][Br:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Br-:30].[OH:10][C:9]([C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)([C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: OC(c1ccsc1)(c1ccsc1)C12CCN(CC1)CC2
Reactant: BrCCOc1ccccc1
Solvent: ClC(Cl)Cl
Product: OC(c1ccsc1)(c1ccsc1)C12CC[N+](CCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 54.3 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-3-thienyl)methanol (0.0787 g, 0.258 mmol) and 2-bromoethyl phenyl ether (0.0839 g, 0.417 mmol) in 2MeOH/3 CHCl3/2 CH3CN (5.0 mL) were reacted to give the desired product (0.0709 g, 54.5%). EI-MS m/z 426(M+) Rt (1.85 min).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([Br:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: CNC
Reactant: O=C(Cl)Cc1cc(Br)ccc1I
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1cc(Br)ccc1I

Procedure:
Dimethylamine (200 mL of 2 M in THF) is added dropwise to a solution of the above 5-bromo-2-iodophenylacetyl chloride in Et2O (500 mL), cooled in an ice bath. After the addition is complete, EtOAc (350 mL) is added and the solution washed with water (350 mL), brine (250 mL) and dried (MgSO4). Evaporation by rotary evaporator and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-bromo-2-iodophenylacetamide (m.p. 127–129° C.).
Reaction SMILES: [CH3:1][C:2]1(Br)[CH2:4][CH2:3]1.[S:6]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O-:9])(=[O:8])=[S:7].[K+]>C(O)C>[CH:4]1([CH2:3][O:9][S:6]([C:10]2[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=2)(=[S:7])=[O:8])[CH2:2][CH2:1]1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Reactant: CC1(Br)CC1
Agent: [K+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=S)OCC2CC2)cc1
Temperature: 90 °C
Yield: 72.5 %

Procedure:
To a solution of methylcyclopropyl bromide (4.00 g, 29.6 mmol) in ethanol (20.0 mL) was added potassium thiotosylate (10.0 g, 44.4 mmol) and the mixture heated to 90° C. for 10 h. The mixture was then quenched into a 1:1 mixture of H2O (50.0 mL) and diethyl ether (50.0 mL). The layers were separated and the organic layer washed with brine (50.0 mL). The organic layer was then dried with MgSO4 and concentrated in vacuo to yield the title compound as a solid (5.2 g, m.p. 46°-48° C.). 1H NMR (400 MHz, CDCl3) δ 7.816 (d, 2 H, J=8.8 Hz), 7.308 (d, 2 H, J=8.8 Hz), 2.945 (d, 2 H, J=7.6 Hz), 2.451 (s, 3 H), 1.010-0.933 (m, 1 H), 0.592-0.545 (m, 2 H), 0.236-0.197 (m, 2 H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:33][C:34]1([F:44])[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:33][C:34]1([F:44])[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[CH2:20][O:21][C:22]2[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:42])[CH2:36][CH2:35]1
Reactant: O=C(O)CC1CCC(F)(F)CC1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)CC1CCC(F)(F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 2-(4,4-difluorocyclohexyl)acetic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Pd].C(O)C>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(-c2ccc(N)cc2)cc1
Yield: 67 %

Procedure:
4′-Nitro-4-n-octyl-biphenyl (1.2 g, 3.9 mmol) was added to a suspension of palladium on carbon (Pd/C, 1.0 g) in a mixed solvent of THF (60 mL) and ethanol (24 mL). The preparation was hydrogenized under constant hydrogen flow for 3 hours. The catalyst was filtered out, and the volatiles were removed in vacuo to give a pale yellow oil. Chromatography on silica gel gave 4-n-octyl-4′-amino-biphenyl as a colorless oil, which solidified upon standing (0.75 g, 67% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[N:6]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(C)C)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)c1cc(C(C)C)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 3,5-Diisopropyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.92–7.0 (m, 2H), 6.80–6.88 (dd, 2H), 5.88 (s, 1H), 4.92 (s, 2H), 3.70–3.80 (t, 4H), 2.90–3.10 (m, 4H), 1.40–1.60 (m, 12H). 13C NMR (400 MHz, CDCl3): 160.6, 158.2, 150.2, 119.2, 118.0, 100.0, 50.8, 50.5, 50.2, 45.2, 42, 28.2, 26.0, 22.4.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>C(OCC)C.CO>[OH:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][OH:25])[C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCNCCO
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CCO
Temperature: 0 °C

Procedure:
A solution of 2.75 g palmitoyl chloride (10 mmol) in 20 ml anhydrous ethylether is added drop by drop in 30 minutes to a solution of 2.2 g diethanolamine (21 mmol) in 50 ml methanol and 100 ml anhydrous ethyl ether under continuous stirring at 0° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[NH:13][CH:12]([C:14]([OH:16])=O)[CH2:11][S:10]1.Cl.CN(CCCN=C=NCC)C.[N+]([O-])(O)=O.[CH3:33][NH:34][CH2:35][CH2:36][O:37][N+:38]([O-:40])=[O:39]>CN(C)C=O>[OH2:8].[CH3:33][N:34]([CH2:35][CH2:36][O:37][N+:38]([O-:40])=[O:39])[C:14]([CH:12]1[CH2:11][S:10][C:9](=[O:8])[NH:13]1)=[O:16]
Reactant: O=C1NC(C(=O)O)CS1
Reactant: CNCCO[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=[N+]([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(CCO[N+](=O)[O-])C(=O)C1CSC(=O)N1
Product: O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 5.5 %

Procedure:
0.95 ml of triethylamine, 1.0 g of 2-oxothiazolidine-4-carboxylic acid and 1.30 g of 1-(N,N-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, whilst ice-cooling and stirring, to a suspension of 1.24 g of N-methyl-N-(2-nitrooxyethyl)amine nitrate in 50 ml of dry N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 45 minutes, after which the solvent was removed by distillation under reduced pressure. The residue was mixed with ethyl acetate, and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residual yellow oil was purified by column chromatography through silica gel, using a 4:1 by volume mixture of methylene chloride and ethyl acetate as the eluent. The colorless oil thus obtained was triturated with a small amount of tetrahydrofuran to induce crystallization. The crystals which precipitated were collected by filtration and recrystallized from acetone, to give 50 mg of the title compound as colorless crystals, melting at 110°-112° C.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][OH:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[Cl-].[NH4+]>COCCOC>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]([OH:33])[C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: NC(=O)C(=O)O
Reactant: COc1ccc(CCNO)cc1OC
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: COc1ccc(CCN(O)C(=O)C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-hydroxamide. To a suspension of oxamic acid (195 mg, 2.21 mmol) in 1,2-dimethoxyethane (7 mL) under an argon atmosphere was added dropwise N-methylmorpholine (0.27 mL, 2.42 mmol), followed by ethyl chloroformate (0.23 mL, 2.42 mmol). After stirring for 1 h at room temperature, a solution of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hydroxyamine (417 mg, 2.10 mmol) in 1,2-dimethoxyethane (5 mL) was added, and the resulting mixture was stirred for 4 h. Saturated aqueous ammonium chloride was added, and the mixture was extracted with methylene chloride (2×). The combined organic extracts were washed successively with 10% hydrochloric acid and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 5% methanol/methylene chloride, and recrystallized from methanol/methylene chloride to provide the oxamide (98 mg, 17%): m.p. 143°-144° C.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.CS([Cl:14])(=O)=O.[Cl:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:25](=[O:38])[C:26]3[CH:35]=[C:34]([CH2:36]O)[S:33][C:27]=3[N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)=[O:23])=[CH:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][NH:21][C:22]([C:24]2[C:25](=[O:38])[C:26]3[CH:35]=[C:34]([CH2:36][Cl:14])[S:33][C:27]=3[N:28]([CH2:30][CH2:31][CH3:32])[CH:29]=2)=[O:23])=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)sc21
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Product: CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-N,N-Dimethylaminopyridine (80 mg), 2,4,6-collidine (1.39 mL), and methanesulfonyl chloride (0.81 mL) are added to a solution of N-(4-chlorobenzyl)-7-propyl-2-(hydroxymethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 12, 1.63 g) in anhydrous DMF (80 mL). The reaction mixture is stirred at room temperature for 24 h. The mixture is diluted with water (150 mL) and filtered. The resulting light yellow powder is recrystallized from acetonitrile and dried in a vacuum oven to afford 1.4 g of the title compound as a light yellow solid. Physical characteristics. Mp 186.5-188° C.; 1H NMR (300 Mhz,7 DMSO-6) δ 10.45, 8.75, 7.56, 7.39, 5.15, 4.54, 4.27, 1.85, 0.91. Anal. Found: C, 55.76; H, 4.59; N, 6.95; Cl, 16.88; S, 7.80.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][O:33][CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][CH2:35][CH2:34][O:33][CH3:32])=[CH:24][C:23]=3[F:31])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: COCCN
Reactant: Cc1c(Oc2ccc(C(=O)O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1ccc(Oc2ncnc(OC3CCN(C(=O)OC(C)C)CC3)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (150 mg, 0.346 mmol), 2-Methoxy-ethylamine (31 mg, 0.41 mmol), HATU (157 mg, 0.42 mmol) and triethyl amine (70 mg, 0.7 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was purified through HPLC to provide Compound C122 (115 mg, 68%) as a solid. 1H NMR (MeOH-d4, 400 MHz) δ 1.22 (d, J=6.82 Hz, 6H), 1.71-1.74 (m, 2H), 1.97-2.00 (m, 2H), 2.16 (s, 3H), 3.34 (s, 3H), 3.35-3.39 (m, 2H), 3.53 (s, 4H), 3.71-3.74 (m, 2H), 4.81-4.84 (m, 1H), 5.33-5.36 (m, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.66-7.69 (m, 2H), 8.09 (s, 1H). Exact mass calculated for C24H31FN4O6490.2, found 491.4 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O.[ClH:24]>O.C1C=CC=CC=1>[Cl:24][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][Cl:22]
Reactant: O=S(Cl)Cl
Reactant: OCCOCCOCCOCCO
Reactant: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: ClCCOCCOCCOCCCl
Reaction time: 3 h

Procedure:
A mixture of 430 g of tetraethylene glycol (2.2 moles), 2000 ml of dry benzene, and 386 g of pyridine (4.9 moles) is heated to reflux, and 580 g of thionyl chloride (4.9 moles) is added dropwise with stirring in three hours. During this period the reflux temperature of the mixture drops from 86° to 78°, and a white precipitate is formed. Heating is continued overnight (16 hours) and, after cooling, 50 ml of hydrochloric acid diluted with 200 ml of water is added dropwise in about 15 minutes. Benzene is removed from the upper layer containing the product, and the residue vacuum distilled at 4.5 mm Hg at 165°. The yield is 375 g of light yellow liquid (72%).