Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[C:5]([C:11]([OH:13])=O)[CH:4]=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[C:6]=5[C:7]([F:10])([F:9])[F:8])=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c1C(F)(F)F
Yield: 64.7 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (71.0 mg, 65%) was obtained as a white solid.
Reaction SMILES: C(C1N(C2C(F)=CC=CC=2Cl)C(C=O)=C(C)N=1)CCC.[H-].[Na+].[CH2:23]([C:27]1[N:28]([CH2:45][C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:53])[C:29](/[CH:32]=[C:33](\[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)/[C:34]([O:36]C)=[O:35])=[CH:30][N:31]=1)[CH2:24][CH2:25][CH3:26].C(C1N(CC2C=CC=CC=2Cl)C(/C(/C)=C/C(O)=O)=CN=1)CCC>C(OCC)(=O)C.CCCCCC.C(COC)OC>[CH2:23]([C:27]1[N:28]([CH2:45][C:46]2[C:51]([F:52])=[CH:50][CH:49]=[CH:48][C:47]=2[Cl:53])[C:29](/[CH:32]=[C:33](\[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)/[C:34]([OH:36])=[O:35])=[CH:30][N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)OC)n1Cc1c(F)cccc1Cl
Agent: CCCCc1nc(C)c(C=O)n1-c1c(F)cccc1Cl
Agent: CCCCc1ncc(/C(C)=C/C(=O)O)n1Cc1ccccc1Cl
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: COCCOC
Product: CCCCc1ncc(/C=C(\Cc2ccccc2)C(=O)O)n1Cc1c(F)cccc1Cl
Yield: 91 %

Procedure:
The procedure of Example 1(iv-v) was used. From 0.9 g (3.05 mmol) of 2-n-butyl-1-(2-chloro-6-fluorophenyl)-methyl-1H-imidazol-5-carboxaldehyde, 3 g (11 mol) of trimethyl benzylphosphonoacetate, 0.28 g of sodium hydride and glyme (12 mL) held at 60° C. for 1 hour was obtained, after chromatography over silica gel with 50% of hexane in ethyl acetate, 0.44 g (33%) of the trans isomer methyl (E)-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl} -1H-imidazol-5-yl]-2-benzyl-2-propenoate and 0.01 g (8%) of the corresponding cis or (Z)-isomer. The (E)-isomer(0.43 g, 0.98 mmol) was hydrolyzed to the acid and the product was crystallized from methanol to afford 0.38 g (91%) of (E)-3-[2-n-butyl-1-{(2-chloro-6-fluorophenyl)methyl}-1H-imidazol-5-yl]-2-benzyl-2-propenoic acid; mp 204°-206° C.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CO.C(N(CC)CC)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 2-bromomethyl-benzoic acid methyl ester (1.50 g, 6.55 mmol, 1.0 equiv; [CAS RN 2417-73-4]) in methanol (12.5 mL) and triethylamine (1.10 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.38 g, 6.88 mmol, 1.05 equiv; commercially available) and the reaction stirred at rt overnight. The reaction mixture was poured on crashed ice, extracted with ethyl acetate, the combined organic phases washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with hexane/ethyl acetate (1:1) followed by crystallization from hexane/ethyl acetate to obtain 1.12 g (54%) of the title compound as white crystals. MS (ISP): 261.0 [M-tert-Bu+H]+.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[C:30]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=[O:36])#[N:31]>[Cl-].[NH4+].C(OCC)(=O)C>[OH:36][CH:35]([C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][Si:8]([CH:15]([CH3:17])[CH3:16])([CH:12]([CH3:14])[CH3:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1)[C:34]1[CH:33]=[C:32]([CH:39]=[CH:38][CH:37]=1)[C:30]#[N:31]
Reactant: CC(C)[Si](OCc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: N#Cc1cccc(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCc1ccc(C(O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 74.4 %

Procedure:
Stir a solution of (4-bromo-benzyloxy)-triisopropyl-silane (72 g, 209.7 mmol) and tetrahydrofuran (500 mL) at −78° C. Add a 1.6 M solution of n-butyllithium in hexanes (143 mL) over 10 min. After addition, allow the reaction mixture to reach −20° C. and stir for 5 minutes. Cool the reaction mixture to −78° C. In another flask, stir a solution of 3-cyanobenzaldehyde (25 g, 190.6 mmol) and tetrahydrofuran (250 mL) at −78° C. Add the lithium anion solution to the aldehyde solution via large canula at a rate such that the internal aldehyde temperature does not rise above −50° C. After addition is complete, stir the reaction mixture 18 hours at room temperature. Dilute the reaction mixture with aqueous saturated ammonium chloride (500 mL) and ethyl acetate (200 mL). Separate the layers, and extract the aqueous layer with ethyl acetate (3×100 mL). Combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue via silica gel chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to afford the title compound (56.1 g, 75%) as a colorless oil. LCMS (m/z) 396 M+1.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH2:11])=[N:8][CH:7]=1.CCN(C(C)C)C(C)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6]1[S:10][C:9]([NH:11][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=2)=[O:32])=[N:8][CH:7]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)Cc1cnc(N)s1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Reaction time: 8 h

Procedure:
To a solution of the HBr salt of (2-amino-thiazol-5-yl)-acetic acid methyl ester (compound 44.1; 20 mmol) in DIEA (40 mmol) and DMF (100 mL) was added 3-trifluoromethylphenyl isocyanate (20 mmol) at room temperature. After overnight stirring, the reaction mixture was concentrated and purified by flash column chromatography on silica gel to provide {2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-acetic acid methyl ester (compound 44.2) in 60% yield. EIMS (m/z): calcd. for C14H12F3N3O3S (M+)+H 360.06. found 360.10.
Reaction SMILES: C([O:8][P:9]([O:19][C:20]1[C:21]([OH:43])=[C:22]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:23]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:24]=1[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[CH3:28][N:26]([CH3:27])[C:25]([C:24]1[N:23]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:22]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:21]([OH:43])[C:20]=1[O:19][P:9]([OH:10])([OH:11])=[O:8])=[O:29]
Reactant: CCOC(=O)c1c(O)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(OP(=O)(O)O)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Yield: 95.3 %

Procedure:
A solution of ethyl 4-((bis(benzyloxy)phosphoryl)oxy)-5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (26) (225 mg, 0.37 mmol) in MeOH (10 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford ethyl 5-(dimethylcarbamoyl)-3-hydroxy-1-(4-methoxyphenyl)-4-(phosphonooxy)-1H-pyrrole-2-carboxylate (UL1-070) (151 mg, 94%) as a pale yellow solid: m/z 429 (M+H)+ (ES+); 427 (M−H)− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 7.11-7.03 (m, 2H), 6.93-6.85 (m, 2H), 3.99 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.82 (s, 3H), 2.71 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:25])[C:9]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13][C:12]([CH3:18])([CH:15]=[N:16]O)[CH2:11][CH2:10]1>C1COCC1>[NH2:16][CH2:15][C:12]1([CH3:18])[CH2:11][CH2:10][C:9]([N:8]([CH3:25])[CH3:7])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:14][CH2:13]1
Reactant: CN(C)C1(c2ccccc2)CCC(C)(C=NO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(C)(CN)CC1

Procedure:
Lithium aluminium hydride (1.82 g, 48.0 mmol) was suspended in abs. THF (200 mL) in argon, mixed in drops with a solution of the title compound from step 3 (6.25 g, 24.0 mmol) in abs. THF (20 mL) and boiled for 4 h with reflux. The batch was then hydrolysed with water (20 mL) at 10° C. and filtered off over diatomaceous earth. The THF was removed in a vacuum, the residue adjusted to pH 11 with 1N NaOH and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, concentrated to low volume in a vacuum and the remaining residue separated by flash chromatography with MeOH+1% NH3.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:16].OO.NC(N)=O>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N+:4]([O-:16])[CH:3]=1
Reactant: CCOC(=O)c1ncc(Br)cn1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Br)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 0° C. cooled solution of 1-ethyl 5-bromopyrimidine-2-carboxylate (2, 1.5 g, 6.5 mmol) in dichloromethane (30 mL), trifluoroacetic anhydride (13.69 g, 65 mmol) and Urea hydrogen peroxide (6.1 g, 65 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. TLC showed consumption of starting material, the reaction mixture was diluted with water (10 mL) and neutralized with solid sodium bicarbonate. The solution was extracted with dichloromethane (2×40 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 5-bromo-2-(ethoxycarbonyl) pyrimidine 1-oxide (3) as yellow liquid which was used without further purification. Yield: 0.64 g, crude; MS (ESI) m/z 247.13 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:33]([N:38]([CH3:46])[C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])[C@@H:34]([CH3:37])[CH2:35][CH3:36])[CH2:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:15])=[O:6].[CH:47]1[C:59]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:70])([C:67](O)=[O:68])[CH3:66])=[O:63])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:56]1[C:57]2[CH:58]([CH2:60][O:61][C:62]([N:64]([CH3:71])[C:65]([CH3:66])([C:67]([NH:41][C@H:40]([C:39]([N:38]([C@@H:33]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[C@H:12]([O:31][CH3:32])[C@@H:13]([CH3:30])[C:14]([NH:16][C@H:17]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[S:15])=[O:6])[CH3:46])=[O:45])[CH:42]([CH3:44])[CH3:43])=[O:68])[CH3:70])=[O:63])[C:59]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:52]=2[CH:53]=[CH:54][CH:55]=1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #82 (670 mg, ≦0.818 mmol, 1 eq.), dichloromethane (5 mL, 0.16 M), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (304 mg, 0.896 mmol, 1.1 eq.), HATU (372 mg, 0.978 mmol, 1.2 eq.) and diisopropylethylamine (440 μL, 2.53 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 30% acetone in heptane) to give #83 (556 mg, 69% over two steps). LC-MS: m/z 994.7 [M+H+], retention time=0.69 minutes; HPLC (Protocol C): retention time=9.333 minutes (purity >98%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.53 (br d, J=8 Hz) and 10.80 (br d, J=8 Hz), total 1H], 7.86-7.91 (m, 2H), [7.80 (d, J=3.3 Hz) and 7.82 (d, J=3.2 Hz), total 1H], [7.64 (d, J=3.2 Hz) and 7.68 (d, J=3.2 Hz), total 1H], 7.62-7.66 (m, 2H), 7.38-7.44 (m, 2H), 7.28-7.36 (m, 5H), 7.19-7.26 (m, 2H), 7.12-7.17 (m, 1H), [6.31 (ddd, J=11, 8, 4.5 Hz) and 6.44 (ddd, J=11, 8.5, 4.5 Hz), total 1H], [4.42 (dd, J=9, 8 Hz) and 4.48 (dd, J=8, 8 Hz), total 1H], 3.22 and 3.24 (2 s, total 3H), 3.13 and 3.17 (2 s, total 3H), 2.89 and 2.97 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), [1.13 (d, J=6.4 Hz) and 1.16 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].Cl[C:18](=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C)C(=O)C.C(OCC)C.C(OCC)(=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:25])[CH3:24]
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
2-Amino-5-methanesulfonylamino-benzenesulfonamide (23.27 g, 87.81 mmol) was dissolved in N,N-dimethylacetamide (100 mL) and diethyl ether (100 mL). Ethyl 3-chloro-3-oxo-propionate (13.88 g, 92.20 mmol) was added and the reaction mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with ethyl acetate (400 mL) and was extracted with water (400 mL). The aqueous layer was back-extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and most of the solvent was removed in vacuo to a volume of ˜100 mL. To the stirred solution was added hexanes (˜100 mL) upon which a precipitate formed. The precipitate was collected by vacuum filtration, washed with hexanes and dried under high vacuum to afford the analytically pure product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (31.22 g, 85.53 mmol, 97.4% yield) as a light-brown solid. 1H NMR (400 MHz, CD3OD) δ: 1.31 (3H, t, J=7.0 Hz), 3.00 (3H, s), 3.59 (2H, s), 4.25 (2H, quartet, J=6.9 Hz), 7.42-7.45 (1H, m), 7.86 (1H, m), 7.92 (1H, d, J=8.8 Hz).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=3[CH:30]=[O:31])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C1C[O:41]CC1.Cl([O-])=O.[Na+].S(=O)(=O)(O)N>O>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][C:20]=3[C:30]([OH:41])=[O:31])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C=O)c1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3.10 g (6.28 mmol) of ethyl 4-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-3-formylbenzoate are introduced into 50 ml of THF. At about 0° C. (internal temperature), solutions of 2.13 g (18.8 nmol) of sodium chlorite in 2.5 ml of water and 1.83 g (18.8 mmol) of sulphamic acid in 9 ml of water are simultaneously added dropwise. The mixture is then stirred at 0° C. for 15 minutes. The reaction mixture is added to 120 ml of water and extracted with ethyl acetate (four times 60 ml). The combined organic phases are washed with saturated sodium chloride solution (twice 50 ml). A finely dispersed precipitate is evident in the organic phase. 300 ml of dichloromethane are added, and the solution is dried over sodium sulphate and concentrated. The resulting product (2.96 g) is reacted without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:9])[CH2:3]1>CC(C)=O>[C:4]1(=[O:9])[CH2:5][CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3]1
Reactant: O=C1CCCCC(O)C1
Solvent: CC(C)=O
Product: O=C1CCCCC(=O)C1
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a 10°-20° C. solution of 20 g. (0.156 mole) of 3-hydroxycycloheptanone in 700 ml. of acetone was slowly added 54.9 ml. of 2.67 M Jone's reagent (0.146 mole). The mixture was stirred 15 minutes and then quenched by addition of 12 ml. of isopropanol. The reaction was filtered through diatomaceous earth and the filtrate concentrated on a rotovapor to about 100 ml. The residue was diluted with 300 ml. of saturated sodium chloride and then extracted with six 250 ml. portions of ether. The combined organic extract was washed with two 100 ml. portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure (aspirator) to yield an oil. Distillation of the crude oil gave 11.5 g. (58%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[C:4]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:3]=1.[CH:15]1([N:20]=[C:21]=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[C:4]([S:11](=[O:13])(=[O:14])[NH:12][C:21](=[S:22])[NH:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:3]=1
Reactant: CC(=O)Nc1sc(Cl)cc1S(N)(=O)=O
Reactant: S=C=NC1CCCC1
Product: CC(=O)Nc1sc(Cl)cc1S(=O)(=O)NC(=S)NC1CCCC1

Procedure:
The title compound was prepared from N-(5-chloro-3-sulfamoylthiophen-2-yl)-acetamide and cyclopentyl isothiocyanate by a procedure analogous to the procedure described in example 15a (yield of crude product: 93%); 1H-NMR (DMSO-d6): δ1.3-2.0 (m, 8H, (CH2)4), 2.28 (s, 3H, CH3), 4.32 (sext, 1H, CH), 7.16 (s, 1H, H-4), 8.48 (br d, 1H, NH), 10.23 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:4].[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:1][C:2]([F:31])([F:30])[C:3]([N:5]([CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([C:36]2[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=2)=[CH:11][CH:10]=1)=[O:4]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccc(I)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccc([C@@H]3C[C@H]3N(CC3CCN(C(=O)OC(C)(C)C)CC3)C(=O)C(F)(F)F)cc2)cn1
Temperature: 85 °C
Reaction time: 4 h
Yield: 43.6 %

Procedure:
To a 10-mL microwave tube were added tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-(4-iodophenyl)cyclopropyl)acetamido)methyl)piperidine-1-carboxylate (300 mg, 0.543 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (136 mg, 0.652 mmol), potassium carbonate (263 mg, 1.901 mmol), acetonitrile (2 mL) and water (0.500 mL), and the mixture was degassed by bubbling N2 through. Tetrakis (31.4 mg, 0.027 mmol) was added and the tube was sealed. The mixture was stirred at 85° C. for 4 h. The mixture was cooled and concentrated. The residue was purified using column chromatography (silica gel, 0 to 100% EtOAc/hexanes) to give 120 mg of product as pale yellow solid. MS: (M+H)+=507.5. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.08-1.20 (m, 2H), 1.43-1.54 (m, 10H), 1.57-1.78 (m, 3H), 1.95-2.10 (m, 2H), 2.40-2.86 (m, 3H), 3.16 (d, J=3.54 Hz, 1H), 3.38-3.63 (m, 2H), 3.90-3.98 (m, 3H), 4.00-4.19 (m, 2H), 7.09-7.18 (m, 2H), 7.46-7.55 (m, 2H), 7.77-7.84 (m, 1H), 7.90-7.97 (m, 1H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1([O:15][CH2:14][CH2:13][O:12]1)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl-].[Li+].S(Cl)([Cl:21])(=O)=O.C(OC(C)C)(C)C>C(O)(=O)C.O>[CH3:1][O:2][N:3]=[C:4]([C:10]1([O:12][CH2:13][CH2:14][O:15]1)[CH2:11][Cl:21])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1(C)OCCO1
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)OC(C)C
Product: CCOC(=O)C(=NOC)C1(CCl)OCCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 2-methoxyimino-3,3-ethylenedioxybutyrate (syn isomer, 30 g) in acetic acid (150 ml) was added lithium chloride (7 g) and the mixture was stirred for 15 minutes at ambient temperature. To the mixture was added dropwise sulfuryl chloride (22.4 g), and the mixture was stirred for one hour at ambient temperature and then allowed to stand for overnight. To the reaction mixture was added water (600 ml) under ice-cooling and stirring, and diisopropyl ether (400 ml) was added thereto and then stirred. The diisopropyl ether layer was separated, and the remaining aqueous layer was further extracted with diisopropyl ether. The diisopropyl ether layer and extract were combined together, washed with water, a saturated aqueous solution of sodium bicarbonate, water and a saturated aqueous solution of sodium chloride in turn, dried over magnesium sulfate and then filtered. The filtrate was concentrated and the residual oil (31.2 g) was distilled under reduced pressure to give ethyl 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyrate (syn isomer), bp 104°-106° C./0.32-0.35 mmHg.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)([CH3:3])[CH3:2].[C:10](Cl)(=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Yield: 86.9 %

Procedure:
Following the procedure described in Referential Example 3, but using 4-(S)-isopropyl-2-oxazolidinone (5.39 g) and dodecanoyl chloride (9.46 g), the desired compound (11.3 g) was obtained as a colorless oil.