Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.[OH-].[Na+].CO>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O)c12

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (Intermediate III) (1.0 g), sodium hydroxide 1M (10 ml), methanol (20 ml) and THF (20 ml) were stirred at rt overnight. The mixture was concentrated and diluted with EE and water. The aqueous layer was acidified with hydrochloric acid and filtrated.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[S:20][CH:21]=[C:22]([Br:24])[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]>C(O)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[S:20][CH:21]=[C:22]([Br:24])[CH:23]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@H:6]([CH3:25])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@H]1C
Solvent: CCO
Product: C=CCN1C[C@@H](C)N([C@@H](c2cccc(O)c2)c2cc(Br)cs2)C[C@@H]1C
Yield: 21.1 %

Procedure:
A solution of 4.22 g (11 mmol) of (-)-p-ditoluoyl-L-tartaric acid in 15 mL of absolute ethanol was added to a suspension of 2.3 g (5.5 mmol) of (±)-3-((R*)-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)-methyl)phenol (Example 42) in 5 mL of absolute ethanol. The mixture was heated to boiling and the resulting clear solution was allowed to crystallize at room temperature. After three crystallizations, the salt was converted to the free amine as in Example 65 and recrystallized from absolute ethanol to give 0.490 g (43% of theoretical for one enantiomer) of (+)-3-((S)-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)(4-bromo-2-thienyl)methyl)phenol as white crystals, mp 183°-185° C. Absolute configuration was determined by x-ray crystallography. [α]D20 =+14.5° (tetrahydrofuran, c=3.3). HPLC on β-cyclodextrin with methanol: 0.1M ammonium acetate/1:1 gave one peak at tR =11 min. Calc. for C20H25BrN2OS: C, 57.00; H, 5.98; N, 6.65; Br, 18.96; S, 7.61. Found: C, 56.93; H, 5.99; N, 6.67; Br, 19.04; S, 7.67.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:30])([F:29])[C:24](=[CH2:28])[C:25]([OH:27])=[O:26].N([O-])=O.[Na+].[ClH:35]>CC(C)=O.[Cu]Cl>[Cl:35][C:24]([C:23]([F:30])([F:29])[F:22])([CH2:28][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([F:21])[CH:3]=1)[C:25]([OH:27])=[O:26]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(N)cc2F)c1=O
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(CC(Cl)(C(=O)O)C(F)(F)F)cc2F)c1=O

Procedure:
This compound was prepared in a manner analogous to that of Step E of Example 1, using 6.0 grams (0.020 mole) of 3-(4-amino-2-fluorophenyl)-1-methyl-6-trifluoromethyluracil (prepared as in Step D of Example 1), 28.0 grams (0.200 mole) of 2-trifluoromethylpropenoic acid, 1.4 grams (0.020 mole) of sodium nitrite, 0.5 gram (0.005 mole) of copper(I) chloride, and 30 mL of concentrated hydrochloric acid in 150 mL of acetone, yielding 5.8 grams of 2-chloro-2-trifluoromethyl-3-[3-fluoro-4-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl]propanoic acid. The NMR spectrum was consistent with the proposed structure. This reaction differed from Step E of Example 1 in that the intermediate propene used here was the acid, rather than the methyl ester, as was used in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)=[CH:5][CH:4]=1.[N+](C1C=CC=CC=1S([N:26]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=O)=O)([O-])=O.[BH3-][C:44]#[N:45].[Na+].C(OC)(OC)OC>CO.C(O)(=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][N:35]([CH2:28][C:27]2[NH:26][CH:36]=[CH:44][N:45]=2)[CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: [BH3-]C#N
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: COC(OC)OC
Product: COc1ccc2c(c1)CC(N(Cc1ccc(CNCc3ccccn3)cc1)Cc1ncc[nH]1)CC2
Yield: 183.8 %

Procedure:
Using general procedure G: Reaction of 7-methoxy-2-tetralone (299 mg, 1.70 mmol) and N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (500 mg, 1.21 mmol) with NaBH3CN (296 mg, 4.72 mmol) in a mixture of MeOH (15 mL), trimethyl orthoformate (8.5 mL) and acetic acid (15 drops) for 3.5 hours followed by purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the desired product (520 mg, 75%) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[S:21][CH2:22][CH2:23][C:24]([OH:26])=O)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[C:49]([NH2:53])([CH3:52])([CH3:51])[CH3:50]>C(Cl)Cl.CC#N>[C:49]([NH:53][C:24]([CH2:23][CH2:22][S:21][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)N
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 1 h

Procedure:
To a solution of di-acid (Step 2) (55 g, 0.114 mol.), triethylamine (35 mL), in CH2Cl2 (2.8 l) and CH3CN (500 mL) at 0° was added 2-chloro-1-methylpyridinium iodide (32 g, 0.126 m). The suspension was stirred 1 hr at 0° to afford a yellow solution. To this solution was added t-butylamine (14 mL). The reaction was stirred at room temperature overnight. The mixture was then evaporated, and partitioned between ethyl acetate and H2O. The aqueous phase was adjusted to pH 3-4 before extraction. The organic phase was dried and evaporated. Flash chromatography of the residue using 15% acetone and 0.2% AcOH in toluene afforded the title compound as an oil. Trituration with ethanol afforded the title compound as a white solid which was further purified by swishing in ether.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]3[N:28]=[N:29][NH:30][N:22]=3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C#N)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1cccc(-c2cc(-c3nn[nH]n3)cc3[nH]c4ncc(C)cc4c23)c1
Temperature: 158 °C
Yield: 77.5 %

Procedure:
Compound 126 (14 mg, 0.037 mmol), sodium azide (9.7 mg, 0.15 mmol), and ammonium chloride (8.0 mg, 0. 15 mmol) were combined in DMF (1 mL) and heated at 158° C. in the microwave for 1 h. Purification by prep-HPLC gave 12 mg (77%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.02-8.11 (m, 2H), 7.94 (t, 1H, J=5.6 Hz), 7.83 (s, 1H), 7.54 (s, 1H), 3.44 (q, 2H, J=7.2 Hz), 2.27 (s, 3H), 1.17 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H18N6O2S, 419; found 419.
Reaction SMILES: [F:1][C:2]([F:14])([CH:10]([OH:13])[CH2:11][CH3:12])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(Cl)(Cl)Cl.[C:19](Cl)(=[O:23])[C:20]([CH3:22])=[CH2:21].C(N(CC)CC)C>O>[C:19]([O:13][CH:10]([CH2:11][CH3:12])[C:2]([C:3]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:4])([F:14])[F:1])(=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)C(=O)Cl
Reactant: CCC(O)C(F)(F)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(CC)C(F)(F)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A 25 mL reactor was charged with 1.50 g (5.6 mmol) of t-butyl 2,2-difluoro-3-hydroxypentanoate and 15 mL of chloroform, 10 mg of NONFLEX MBP, 1.17 g (11.2 mmol, 2 eq) of methacrylic chloride, and 0.87 g (8.6 mmol, 1.5 eq) of triethylamine, followed by stirring at 55° C. for 24 hr. Then, 15 mL of water was added, followed by extraction with chloroform one time. The obtained organic layer was washed with saturated sodium hydrogencarbonate and water, followed by removal of water with magnesium sulfate. After conducting filtration, chloroform was distilled off, thereby obtaining 1.57 g of the target 1-(t-butoxycarbonyl)-1,1-difluoro-2-butyl methacrylate. Upon this, purity was 58%, and yield was 58%.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:14][CH3:15])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:15][NH:14][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNc1nc(SC)ncc1CO

Procedure:
(4-Methylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanol was prepared by reduction of 4-methylamino-2-methylsulfanylpyrimidine-5-carboxylic acid ethyl ester with lithium aluminiumhydride in tetrahydrofuran (THF) at temperatures ranging from 5° C. to room temperature (RT).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:11][CH:12]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][C:19](=[O:29])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:17])([CH3:16])[CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([C:8]1([CH2:11][CH2:12][N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:29])[CH2:9][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C1(CC=O)CC1
Reactant: CC(C)(C)OC(=O)CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN(CCC1(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
10.5 g (54.7 mmol, 1 eq.) 1-(2-oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester and 13.21 g (1.08 eq.) N-benzylglycine tert-butyl ester were dissolved in 140 ml toluene. 21 g (1.63 eq.) sodium triacetoxyborohydride were added (exotherm from 25° C. to 28° C.) and the reaction mixture was stirred 5 h at room temperature (IPC by GC). A solution of 2 ml (0.64 eq.) acetic acid in 15 ml toluene was added. After 30 min at room temperature, the reaction mixture was cooled to 0° C. and 100 ml sat. aq. sodium hydrogencarbonate solution was added over 40 min (foaming). 50 ml ethyl acetate were added. The mixture was stirred for 30 min at room temperature. The mixture was extracted with 200 ml and a second time with 50 ml ethyl acetate. The organic phases were washed with 50 ml sat. aq. sodium hydrogencarbonate solution followed by 50 ml sat. aq. sodium chloride solution. The organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 21.5 g of the title compound as an oil (ca. 95% yield, corrected for ca 3% residual toluene and 3% amine starting material).
Reaction SMILES: [CH:1]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:13][CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: NC1CCCCCCCCCCC1
Product: O=C(COCC(=O)NC1CCCCCCCCCCC1)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 1-(ii), cyclododecylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-(([2-(cyclododecylamino)-2-oxoethoxy]acetyl)amino)benzoic acid.methyl ester (yield: 92%).
Reaction SMILES: C([BH3-])#N.[Na+].Cl.Cl.[N:7]1([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.CCO>CO>[CH:26]1([CH2:29][N:10]2[CH2:9][CH2:8][N:7]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:12][CH2:11]2)[CH2:28][CH2:27]1
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(CC3CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.26 g (20.0 mmol) sodium cyanoborohydride was added batchwise at RT to a stirred mixture of 1.71 g (5.0 mmol) tert-butyl 4-piperazin-1-yl-piperidine-1-carboxylate dihydrochloride, 0.75 mL (10.0 mmol) cyclopropanecarbaldehyde, 30 mL EtOH and 20 mL MeOH and stirred overnight at RT. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in saturated NaHCO3 solution and extracted erschöpfend with EtOAc. The combined organic phases were dried over Na2SO4, suction filtered, evaporated down under reduced pressure and purified by column chromatography over silica gel.
Reaction SMILES: [C:1]([C:3]1[C:4]([I:22])=[C:5]([C:14](=[O:21])[NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8](Cl)=[O:9])#[N:2].C[NH:24][CH2:25][CH:26]([OH:29])[CH2:27][OH:28].[CH3:30]C(N(C)C)=O>>[OH:29][CH:26]([CH2:27][OH:28])[CH2:25][NH:24][C:8]([C:7]1[C:11]([I:12])=[C:3]([C:4]([I:22])=[C:5]([C:14](=[O:21])[N:15]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH3:30])[C:6]=1[I:13])[C:1]#[N:2])=[O:9]
Reactant: CNCC(O)CO
Reactant: CC(=O)N(C)C
Reactant: N#Cc1c(I)c(C(=O)Cl)c(I)c(C(=O)NCC(O)CO)c1I
Product: CN(CC(O)CO)C(=O)c1c(I)c(C#N)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
6.6 g of 5-cyano-3-[N-(2,3-dihydroxypropyl)carbamoyl]-2,4,6-triiodobenzoic acid chloride is dissolved in 40 ml of dimethylacetamide and combined with 2.3 g of N-methylamino-2,3-propanediol. The mixture is stirred for one hour at room temperature and then concentrated under vacuum. The thus-obtained crude product can be used directly for nitrile saponification. To isolate the pure product the dilute aqueous solution of the crude product is treated with a cation exchange resin and an anion exchange resin, and the filtered solution is concentrated under vacuum to dryness, thus obtaining 5.9 g (81% of theory) of 3-[N-(2,3-dihydroxypropyl)carbamoyl]-5-[N-(2,3-dihydroxypropyl)-N-methylcarbamoyl]-2,4,6-triiodobenzonitrile; mp 215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12].[CH2:21]=[C:22]([CH2:25]O)[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:21]=[C:22]1[CH2:25][N:10]([C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[S:11](=[O:13])(=[O:12])[N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:23]1
Reactant: CCOC(=O)CNS(=O)(=O)Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C=C(CO)CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1CN(CC(=O)OCC)S(=O)(=O)N(c2c(Cl)cc(Cl)cc2Cl)C1
Temperature: -20 °C
Reaction time: 5 h
Yield: 88.8 %

Procedure:
Ethyl 2-((N-(2,4,6-trichlorophenyl)sulfamoyl)amino)acetate (300 mg, 0.83 mmol), 2-methylenepropane-1,3-diol (73 mg, 0.83 mmol) and triphenylphosphine (544 mg, 2.08 mmol) were dissolved in anhydrous THF (30 mL) in a reactor, and then cooled down −20° C. after removal of air in the reactor by purging nitrogen gas. DIAD (420 mg, 2.08 mmol) was dropwisely added to the reaction mixture and agitated for 5 hr at room temperature. The resultant was concentrated under reduced pressure and purified by column chromatography (dichloromethane:hexane:ethyl acetate=5:4:1), finally yielding the title compound (305 mg, 89%, white solid). 1H NMR (300 MHz, CDCl3): δ 7.40 (s, 2H), 5.25 (s, 1H), 5.16 (s, 1H), 4.36 (s, 2H), 4.27-4.20 (m, 4H), 4.08 (s, 2H), 1.33-1.28 (t, 3H, J=7.1, 7.1 Hz).
Reaction SMILES: C([O:4][C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:9])[CH2:6][CH2:7][OH:8])(=O)C.[OH-].[K+].CO.O>C(Cl)(Cl)Cl>[C:11]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:5]([OH:4])([CH3:9])[CH2:6][CH2:7][OH:8]
Reactant: CC(=O)OC(C)(CCO)c1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)(CCO)c1ccccc1-c1ccccc1

Procedure:
2.84 g. of 3-acetoxy-3-p-biphenylyl-1-butanol are boiled for 2 hours with 2 g. of KOH in 50 ml. of methanol, water and chloroform are added and the mixture is worked up to give 3-p-biphenylyl-1,3-butanediol, m.p. 115°-117°.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][O:13][C:14]([CH2:16][C@@H:17]([OH:21])[C:18]([OH:20])=O)=[O:15].C1C=CC2N(O)N=NC=2C=1.[N:32]1([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C=O)C.O>[CH2:41]([O:40][C:38]([N:32]1[CH2:37][CH2:36][N:35]([C:18](=[O:20])[C@H:17]([OH:21])[CH2:16][C:14]([O:13][CH3:12])=[O:15])[CH2:34][CH2:33]1)=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: COC(=O)C[C@@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 32.9 %

Procedure:
EDCI (3.6 g, 19 mmol) was added to a solution of (R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid (2.8 g, 19 mmol) and HOBt (2.6 g, 19 mmol) in DMF (200 mL). After stirring this mixture for 5 min, benzyl piperazine-1-carboxylate (4.2 g, 3.6 mL, 19 mmol) and triethylamine (2.6 mL, 19 mmol) were added and stirred for 3 days at room temperature. The reaction mixture was poured into water and extracted with EtOAc. After washing the organic layers with brine and water, drying over Na2SO4 and concentrating, purification via silica gel chromatography using 0-10% MeOH/CH2Cl2 gave 4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylic acid benzyl ester as an oil (2.19 g, 33%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.31 (m, 5H), 5.15 (s, 2H), 4.79-4.74 (m, 1H), 3.95 (d, J=8.0 Hz, 1H), 3.79-3.74 (m, 1H), 3.74 (s, 3H), 3.71-3.44 (m, 7H), 2.62 (d, J=5.8 Hz, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Nc1ccc(F)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(F)cc4)cc3)c2)o1

Procedure:
N-(4-Fluorophenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-fluorophenylamine using method 1. LCMS; retention time 3.55 min, MH+ 388.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18](O)=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4].CC[N:28](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.N>CN(C=O)C>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([CH2:15][CH:16]=[CH2:17])[C:10]([C:18]([NH2:28])=[O:19])=[N:9][C:8]=2[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[C:6]1=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: C=CCn1c(C(=O)O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: C=CCn1c(C(N)=O)nc2c1c(=O)n(CCCC)c(=O)n2CCCC

Procedure:
A stirred solution of 1,3-dibutyl-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purine-8-carboxylic acid (1.0 g, 2.9 mmol) in anhydrous DMF (10 ml) was sequentially treated with DIPEA (1.1 ml), PyBOP, and 2M NH3 (3.6 ml). After 2 hours the product mixture was partitioned between 2M HCl(aq) and EtOAc. The organic layer was separated, washed with sat. NaHCO3(aq) solution, brine, then dried (MgSO4) and concentrated giving an orange oil (ca. 2 g). The product was purified by Biotage™ chromatography eluting with 5%→40% EtOAc/cyclohexane mixtures. The appropriate fractions were combined and concentrated to give the amide 90% pure (790 mg, 78%). m/z. 392.3[M+formic acid−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([Cl:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)[CH2:33][CH2:34][CH3:35]>>[ClH:46].[CH2:32]([O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])(=[O:45])=[O:44])=[CH:39][CH:38]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(=O)(=O)c2ccccc2)cc1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 4-n-butoxybenzenesulfonylchloride (67 mg, 0.269 mmol) to give 27 mg as purple solid. M+1 559.4 Calcd 559.20; 1HNMR δ 7.77–7.47 (m, 7H), 6.96–6.93 (m, 2H), 6.55 (d, 1H), 6.52 (d, 1H), 6.41 (d, 1H), 4.01 (t, 2H), 3.63 (app t, 2H), 3.43 (app t, 2H), 3.25 (app t, 2H), 3.17 (app t, 2H), 2.11–2.03 (m, 2H), 1.80–1.71 (m, 2H), 1.53–1.45 (m, 2H), 0.98 (t, 3H).