Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]=[C:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[C:20]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)C1C=CC=CC=1.Cl.[H][H].C(O)CCC>CO.[OH-].[Pd+2].[OH-]>[CH3:24][N:22]1[CH:23]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:10](=[N:9][OH:8])[CH2:11][CH2:12]3)[C:20]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:21]1
Reactant: Cn1cc(-c2ccc3c(c2)CCC3=NOCc2ccccc2)c(-c2ccncc2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCCCO
Solvent: CO
Product: Cn1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To 5-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one O-benzyl oxime (2.50 g; Example 3, Step 4) in 60 mL methanol was added 0.89 g palladium hydroxide (20% by weight on carbon) and 6.3 mL 6M hydrochloric acid. A hydrogen-filled balloon was attached to the reaction vessel and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was filtered through celite and the celite was washed with methanol. The filtrate was concentrated under vacuum and the residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The ethyl acetate was washed with brine and evaporated to yield 1.0 g of crude product as a white solid. The aqueous layer was reextracted with two portions of n-butanol. The n-butanol was evaporated under vacuum to afford an additional 0.4 g crude product as a white solid. The solids were combined and washed with two 15 mL portions of water, dissolved in a 1:1 mixture of dichloromethane-methanol, filtered, and the filtrate evaporated under vacuum. The residue was triturated with ethyl acetate and dried to afford 0.98 g (51% yield) of product as a white solid. 1H NMR (CDCl3) was consistent with the desired structure 113. LC/MS showed a peak with a M+1 molecular ion of m/z 305.4 by positive ESI.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[O:17][C:18]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]([F:23])[CH:29]=3)=[CH:19][CH:20]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (99)(125 mg, 0.34 mmol) was coupled to 3-fluoro-phenylboronic acid (48 mg,×0.41 mmol) acid using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Br.Br.[NH2:39][C@H:40]([C:47]([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([NH2:53])=[O:52])=[O:48])[CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1>CN(C=O)C.C(N(CC)CC)C>[CH3:11][C:2]1([CH3:1])[CH2:6][C:5](=[O:7])[CH2:4][CH:3]1[C:8]([NH:39][C@H:40]([C:47]([N:49]1[CH2:56][CH2:55][CH2:54][C@H:50]1[C:51]([NH2:53])=[O:52])=[O:48])[CH2:41][C:42]1[N:46]=[CH:45][NH:44][CH:43]=1)=[O:10]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC1(C)CC(=O)CC1C(=O)O
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)CC1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Yield: 56.1 %

Procedure:
In DMF (2 ml) was dissolved 2,2 dimethyl-4-oxocyclopentanecarboxylic acid [W. H. Perkin, jun., J. F. Thorpe, J. Chem. Soc., 79, 729 (1901)] (100 mg), and HOBT (108 mg) was added to the solution, followed by addition of DCC (145 mg) under cooling at 0° C. The mixture was stirred at 5° C. over night. After addition of L-histidyl-L-prolinamide dihydrobromide (265 mg) followed by addition of triethylamine (0.134 ml), the mixture was stirred at 5° C. for 4 days. After the resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure to dryness and the residue was subjected to silica gel column chromatography. The fractions eluted by chloroform:methanol:ammonia water (90:10:2) were combined and concentrated to dryness to give the title compound (140 mg) was obtained as powders.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][N:16]3[C:17](=[O:26])[C:18]4[C:19](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:21])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(c2ccncc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
A mixture of 1-pyridin-4-yl-piperazine [Org. Lett. 4 (2002) 737-740] (1.0 g, 6.12 mmol), N-(2-bromoethyl)-phthalimide (1.71 g, 6.74 mmol), potassium carbonate (0.85 g, 6.12 mmol), potassium iodide (1.02 g, 6.12 mmol) and dimethyl formamide (10 mL) was stirred at 70° C. for 24 h, then concentrated. The residue was dissolved in water, extracted with dichloromethane, the organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=10:1:0.1 as eluent to yield 1.52 g (74%) of the title compound, as a white solid.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:48])=[CH:30][CH:29]=1.[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][NH2:58])[CH:52]=1>>[F:27][C:28]1[CH:50]=[CH:49][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][CH2:36][N:35]([C:39]3[S:40][C:41]([C:45]([NH:58][CH2:57][C:53]4[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:48])=[CH:30][CH:29]=1
Reactant: Cc1nc(N2CCCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 15 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxotetrahydropyrimidin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a colorless solid in 15% yield: mp 48-50° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.60-8.54 (m, 2H), 7.70 (d, J=7.6 Hz, 1H), 7.31-7.25 (m, 3H), 7.04-6.99 (m, 2H), 6.05-6.01 (m, 1H), 4.59-4.57 (m, 4H), 4.17 (t, J=5.8 Hz, 2H), 3.32 (t, J=5.8 Hz, 2H), 2.62 (s, 3H), 2.11-2.04 (m, 2H); MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([C:17]1[NH:18][CH:19]=[C:20]([N+:22]([O-])=O)[N:21]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl.CN(C)CCCN=C=NCC.[C:37]([O:41][C:42]([NH:44][C:45]([CH3:64])([CH3:63])[C:46]([NH:48][C@H:49]([CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1)[C:50](O)=[O:51])=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>[Pd].O1CCCC1>[C:37]([O:41][C:42]([NH:44][C:45]([CH3:64])([CH3:63])[C:46]([NH:48][C@H:49]([CH2:53][C:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56][CH:55]=1)[C:50]([NH:22][C:20]1[N:21]=[C:17]([CH:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:18][CH:19]=1)=[O:51])=[O:47])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CCOC(=O)C(c1ccc2ccccc2c1)c1nc([N+](=O)[O-])c[nH]1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccc2ccccc2c1)c1nc(NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
A mixture of ethyl 2-(2-naphthyl)-2-(4-nitroimidazolyl)acetate (2.04 grams, 6.27 mmol), tetrahydrofuran (20 mL), and 10% palladium on carbon (2.04 gram) was hydrogenated at ambient temperature and pressure until complete as determined by hplc (20 hours). The catalyst was removed by filtration and rinsed with tetrahydrofuran (10 mL). The filtrate was added to a slurry consisting of 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (1.20 grams, 6.27 mmol), tetrahydrofuran (10 mL), and (2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoic acid (2.44 grams, 6.27 mmol) and stirred 16 hours at ambient temperature. The reaction mixture was partitioned between water (150 mL) and ethyl acetate (3×50 mL). The organic extracts were combined, washed with saturated sodium chloride solution, dried using sodium sulfate, and evaporated. The resulting crude oil was purified by column chromatography on silica gel with hexane:ethyl acetate:methanol (10:10:1) as an eluent giving 1.72 grams (41%) of ethyl 2-(4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino}-3-indol-3-ylpropanoyl amino)imidazolyl]-2-(2-naphthyl)acetate. A 0.2 gram sample was further purified using preparative reverse phase hplc to give 0.16 grams of ethyl 2-[4-((2R)-2-{2-[(tert-butoxy)carbonylamino]-2-methylpropanoylamino)-3-indol-3-ylpropanoyl amino)imidazolyl]-2-(2-naphthyl)acetate for analytical study. MS (FIA) m/z 667.4 [(M+H)+]. Anal. calcd. exact mass for C37H43N6O6 [(M+H)+]=667.3244. Exact mass found by mass spectrometry: C37H43N6O6 [(M+H)+]=667.3254. 1H nmr (CDCl3): 1.25-1.42 (m, 19H), 3.24-3.33 (m, 2H), 4.28-4.33 (m, 2H), 4.98-5.01 (m, 1H), 5.94 (s, 1H), 6.85-7.01(m, 3H), 7.18-7.21 (m, 2H), 7.35-7.39 (m, 2H), 7.49-7.58 (m, 4H), 7.78-7.84 (m, 4H), 8.69 (s, 1H), 10.65 (s, broad, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([NH:20][N:21]=[C:22]([NH2:24])[CH3:23])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([N:24]=[C:22]([NH:21][NH:20][CH:17]([CH3:19])[CH3:18])[CH3:23])=[O:15])[N:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: O=C(O)c1c[nH]c(-c2ccc(Br)cc2F)n1
Reactant: CC(N)=NNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1c[nH]c(-c2ccc(Br)cc2F)n1)NNC(C)C

Procedure:
Scheme 11 shows the synthesis of 5-(2-(4-bromo-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole V from 4-bromo-2-fluorobenzimidamide hydrochloride 12. 3-Chloro-2-oxopropanoic acid and 12 are reacted with base to give 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 30. Alternatively, 3-bromo-2-oxopropanoic acid can be reacted with 12 to give 30. Reaction of 30 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU (N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, 0-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, CAS Ref No. 94790-37-1) in DMF gives intermediate, 2-(4-bromo-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 31 which need not be isolated and cyclizes upon heating to give V. Alternatively, 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44, the chloro version of V, can be prepared from 4-chloro-2-fluorobenzonitrile 38 (Scheme 15)
Reaction SMILES: [CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[O:26])=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[SH2:44]>C(N(CC)CC)C>[CH2:1]([S:5]([NH:8][C@@H:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([C:35](=[S:44])[NH2:36])=[CH:31][CH:30]=2)=[O:26])=[CH:20][CH:19]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)N[C@@H](Cc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)N[C@@H](Cc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1)C(=O)OC(C)(C)C

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (d) (2.32 g), pyridine (88 ml), triethylamine (13 ml) and H2S gas were reacted to give t-butyl (2S)-2-(n-butylsulphonylamino)-3-[4-[3-(4-thiocarbamoylbenzoyl)ureido]phenyl]propionate (2.4 g) as a yellow solid: NMR Spectrum (DMSO-d6) 0.79 (3H, t), 1.22 (2H, m), 1.38 (11H, m), 2.70 (2H, t), 2.79 (1H, m), 2.95 (1H, m), 3.95 (1H, m), 7.27 (2H, d), 7.53 (2H, d), 7.68 (1H, d), 7.96 (2H, d), 8.03 (2H, d), 9.66 (1H, br s), 10.05 (1H, br s), 10.74 (1H, s), 11.10 (1H, s); Mass Spectrum m/Z 563 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([Cl:28])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][C:19]=3[O:29][CH3:30])[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64].Cl>C(Cl)Cl>[Cl:28][C:24]1[CH:25]=[CH:26][C:27]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15]3[C:20]([O:21][C:22]=2[CH:23]=1)=[C:19]([O:29][CH3:30])[CH:18]=[CH:17][CH:16]=3.[C:63]([OH:69])([C:65]([F:68])([F:67])[F:66])=[O:64]
Reactant: COc1cccc2c1Oc1cc(Cl)ccc1N2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1Oc1cc(Cl)ccc1N2C1CCNCC1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-(3-chloro-6-methoxy-phenoxazin-10-yl)-piperidine-1-carboxylic acid tert-butyl ester, 1p, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound 3-chloro-6-methoxy-10-piperidin-4-yl-10H-phenoxazine, 7p was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH2:8]>>[N:1]1([CH2:8][CH:7]([P:9]([O:13][CH2:14][CH3:15])(=[O:16])[O:10][CH2:11][CH3:12])[P:17]([O:18][CH2:19][CH3:20])(=[O:24])[O:21][CH2:22][CH3:23])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: C1CNCCN1
Product: CCOP(=O)(OCC)C(CN1CCNCC1)P(=O)(OCC)OCC

Procedure:
Reaction of piperazine with tetraethyl ethenylidenebisphosphonate according to the procedure described in Example 1, above, gives tetraethyl 2-(1-piperazyl)-1,1-ethanediphosphonate. Reaction of the latter with 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benz-oxazine-6-carboxylic acid yields the title compound.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][S:24]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][OH:33])(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH:32]=[O:33])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCCC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCC1C=O
Reaction time: 24 h
Yield: 78.1 %

Procedure:
Dess-Martin periodinane (1.7 g, 4 mmol) was added to a solution of (1-(methylsulfonyl)pyrrolidin-2-yl)methanol (0.570 g, 3.18 mmol) in anhydrous methylene chloride (20 mL). The reaction was stirred for 24 hours and a second portion of Dess-Martin periodinane (1 g, 2.3 mmol) was added. The resulting suspension was stirred for 24 hours, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (1-15% ethyl acetate in methylene chloride) to provide a white waxy solid (0.44 g, 78%). 1H NMR (CDCl3, 300 MHz) δ 9.58 (d, 1H, J=1.2 Hz), 4.25-4.20 (td, 1H, J=6.9, 1.2 Hz), 3.55-3.44 (m, 2H), 2.97 (s, 3H), 2.21-2.13 (m, 2H), 2.05-1.90 (m, 2H).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]([CH3:35])[CH2:31][C:32]([OH:34])=O)[CH:26]=[CH:27][C:28]=1[Cl:29].C(N(CC)CC)C>ClCCl>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:32](=[O:34])[CH2:31][N:30]([C:25]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=2)[CH3:35])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c2ccccc2)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (50 mg, 0.18 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (49 mg, 0.21 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexaflurophosphate (BOP) (118 mg, 0.27 mmol) and triethylamine (TEA) (54 mg, 0.54 mmol) in dichloromethane (DCM) (2.0 mL), The reaction mixture was stirred at room temperature for 3 h and was then concentrated in vacuo. To the residue was added 4 mL of saturated solution of Na2CO3 and then extracted by ethyl acetate (2×3 mL). The combined organic layers were concentrated in vacuo to give a brown solid, which was purified by using a Gilson preparative HPLC system (Phenomenex 75×30 mm column, 40 mL/min flow rate, A: 0.1% TFA in acetonitrile B: 0.1% TFA in water, A: 10 to 100% over 15 min, UV detection at 215 nm) to yield the title compound (52 mg, 58%). MS (ES) m/e 496 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[NH:10][S:11](=[O:25])(=[O:24])[N:12]([CH3:23])[CH:13]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[C:14]=3[CH:15]=1)=[N:7][CH:6]=[CH:5][CH:4]=2.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[CH2:61]([O:65]C=C)[CH2:62]CC.Cl>C1COCC1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:13]2[C:14]3[CH:15]=[C:2]([C:61](=[O:65])[CH3:62])[C:3]4[C:8](=[N:7][CH:6]=[CH:5][CH:4]=4)[C:9]=3[NH:10][S:11](=[O:24])(=[O:25])[N:12]2[CH3:23])=[CH:21][CH:20]=1
Reactant: CN1C(c2ccc(F)cc2)c2cc(Br)c3cccnc3c2NS1(=O)=O
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc2c(c3ncccc13)NS(=O)(=O)N(C)C2c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 16.3 %

Procedure:
DMF (2.6 ml) and water (0.6 ml) in a microwave tube were degassed with N2. 9-Bromo-1-(4-fluoro-phenyl)-2-methyl-1,4-dihydro-2H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 399 (100 mg, 0.27 mmol), Pd(OAc)2 (10.6 mg, 0.047 mmol), 1,3-bis(diphenylphosphino)propane (39 mg, 0.09 mmol) and K2CO3 (39 mg, 0.28 mmol) and n-butyl vinylether (154 μl, 1.1 mmol). The mixture was heated in a microwave at 100° C. (200 W, <250 PSi) for 40 min. After cooling, the mixture was diluted with THF (5 ml), acidified with conc. HCl (1 ml) and the mixture was stirred at room temperature for 14 h. The organic phase was diluted with DCM (30 ml), and washed with HCl solution at pH=5-6 (20 ml). The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/EtOAc (95:5) to give the title compound (17 mg, 15%).
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:14])[NH:9][CH2:10][C:11](N)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](I)[CH3:16]>C(O)C>[CH2:15]([S:14][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11](=[O:12])[CH2:10][N:9]=1)[CH3:16]
Reactant: CCI
Reactant: NC(=O)CNC(=S)Nc1ccccc1
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccccc1
Yield: 41.5 %

Procedure:
A mixture of 2-(3-phenyl-thioureido)-acetamide (7.1 g), ethyl iodide (18.0 g), and ethanol (300 mL) was heated at reflux for 2 hours. The solvent was evaporated. The residue was dissolved in chloroform (300 mL) and water (300 mL). The organic phase was washed with water, dried over anhydrous MgSO4, then evaporated to dryness. The residue was crystallized from ethyl acetate/hexane to give the title compound (3.1 g), m.p. 79°-81° C. Anal. Calcd. for. C11H12N2O S: C, 59.97; H, 5.49; N, 12.72. Found: C, 59.67; H, 5.35; N, 12.70. Mass spectrum (EI, M.+) m/z 220. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.43-7.52 (m, 3 H), 7.28-7.31 (m, 2 H), 4.32 (s, 2 H), 3.07 (q, 2 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10](=[O:11])[NH:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:7]=1)=[O:5])C.CO[2H]>>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:8]2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:10](=[O:11])[NH:9]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cn(-c2ccc(OC)cc2)[nH]c1=O
Agent: [2H]OC
Product: COc1ccc(-n2cc(C(=O)O)c(=O)[nH]2)cc1

Procedure:
The ester prepared as described above in (a) was converted to the title acid in a manner analogous to example 11(b). The acid possessed νmax (nujol) 1690, 1670, 1599, 1580, 1575,cm-1, δ(CH3OD|D6DMSO) 3.78 (3H,s,--OMe), 7.00 (2H,d,J9 Hz, protons o to --OMe), 7.66 (2H,d,J9 Hz, protons m to --OMe), 8.45(1H,s, C3 -pyrazole proton). Found: M30, 234.0639; C11H10N2O4 requires M,234.0641.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:20]([CH3:22])[CH3:21])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.5 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) was treated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane (3.85 ml, 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up with ethyl acetate gave the title compound (6.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH:17]([O:23][CH3:24])[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:44]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60]O)[CH:55]=2)[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:46][CH2:45]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:44]1([CH:47]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([CH2:60][O:16][C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:11][C:12]=3[CH:17]([O:23][CH3:24])[CH2:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:55]=2)[CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:46][CH2:45]1
Reactant: COc1ccc(F)c(-c2ccc(O)c(C(CC(C)(C)C)OC)c2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2C(CC(C)(C)C)OC)c1)C1CC1
Yield: 78.4 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-3-(1-methoxy-3,3-dimethylbutyl)-[1,1′-biphenyl]-4-ol (290 mg) in THF (5.0 mL) were added triphenylphosphine (343 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (325 mg) and a 40% solution of diethyl azodicarboxylate in toluene (600 μL), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (385 mg) as a colorless oil.