Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][OH:35])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:48][O:49][CH2:50]Cl.C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([CH2:19][C:20]1([CH2:28][N:29]2[CH:33]=[C:32]([CH2:34][O:35][CH2:48][O:49][CH3:50])[N:31]=[C:30]2[N+:36]([O-:38])=[O:37])[CH2:25][O:24][C:23]([CH3:26])([CH3:27])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:16])([CH3:18])[CH3:17])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COCCl
Reactant: CC1(C)OCC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)(Cn2cc(CO)nc2[N+](=O)[O-])CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOCc1cn(CC2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)COC(C)(C)OC2)c([N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 26 h
Yield: 78.9 %

Procedure:
101 mg (0.19 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-hydroxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 2.0 mL of dichloromethane and cooled to about 0° C. in an ice bath. 125 μL (0.72 mmol equivalents) of N,N-diisopropylethylamine and 41 μL (0.51 mmol equivalents) of methoxymethyl chloride were added thereto, and the mixture was stirred for 26 hours while increasing the temperature to room temperature (25° C.). After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added dropwise, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=2/1) to give 86 mg (0.15 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[(4-methoxymethoxymethyl-2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH:52]([CH3:54])[CH3:53].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:55][CH2:56][CH:57]([CH3:59])[CH3:58])[CH:52]([CH3:54])[CH3:53])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Reactant: CC(C)CSCC(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)CSC(O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of the compound of Example 1 (1.0 g, 1.38 mmol) and diisobutyl sulfide (6.2 mL) in acetonitrile (10 mL) at 0° C. was added benzoyl peroxide (2.0 g) in three portions over 30 minutes, and the reaction was stirred at 0° C. for 1 hour. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with 0-100% ethyl acetate/dichloromethane to provide the title product (0.890 g, 75% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[F:16].[Br:17][C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=1>C1COCC1>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:22]2[CH:23]=[C:18]([Br:17])[CH:19]=[CH:20][C:21]2=[O:24])=[C:10]([F:16])[CH:11]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: Fc1cc(Cl)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1F
Temperature: 60 °C
Reaction time: 17 h
Yield: 82.7 %

Procedure:
According to Scheme 1 Step 2: K2CO3 (10 eq, 0.11 mmol, 16.0 g) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (1.5 eq, 17.0 mmol, 3.90 g) was added to a solution of 5-bromopyridin-2(1H)-one (1 eq, 11.0 mmol, 2.00 g), in THF (100 mL). The suspension was stirred for 2 hours at room temperature and 17 hours at 60° C. The reaction mixture was filtered and the mother liquor was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using CH2Cl2/AcOEt 80/20 as eluent to afford the title compound 1-(4-chloro-2-fluorobenzyl)-5-bromopyridin-2(1H)-one (9.10 mmol, 2.87 g, 79%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][C:18](F)(F)F)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1.[CH:25](=O)CC>>[F:1][C:2]([F:24])([F:23])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:25])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:22])[CH:4]=1
Reactant: CCC=O
Reactant: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC(F)(F)F
Product: CCCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and propionaldehyde. 1H NMR (400 MHz, CDCl3) 11.23 (br. s, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.78 (s, 1H), 3.34 (t, 2H, J=5.6), 3.26 (t, 2H, J=7.4), 2.88 (t, 2H, J=6.3), 1.97 (m, 2H), 1.65 (m, 2H), 0.97 (t, 3H, J=7.4).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH2:8]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:7]=1[NH:8][C:3]([NH:2][CH3:1])=[O:4]
Reactant: CN=C=O
Reactant: Nc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: CNC(=O)Nc1ccc(F)cc1F
Reaction time: 1 h

Procedure:
Methyl isocyanate (9.6 g, 10 mL, 0.174 mol) is added to a solution of 2,4-difluoroaniline (15 g, 0.116 mol) in toluene. The reaction mixture is stirred for 1 hour and filtered to obtain a solid. The solid is washed with hexanes and air-dried to give the title product as an off-white solid, mp 182°-183° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]([C:10]1([C:34]#[N:35])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=O)[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1)[C:8]#[N:9])=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>>[CH2:1]([O:3][C:4]([NH:6][CH:7]([C:10]1([C:34]#[N:35])[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:29](=[S:45])[CH3:30])[O:24][C:23]3=[O:32])=[CH:18][C:17]=2[F:33])[CH2:12][CH2:11]1)[C:8]#[N:9])=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)NC(C#N)C1(C#N)CCN(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)CC1
Product: CCOC(=O)NC(C#N)C1(C#N)CCN(c2ccc(N3C[C@H](CNC(C)=S)OC3=O)cc2F)CC1
Yield: 58 %

Procedure:
By using procedure as described in Example 82 and by reacting (S)-N-{3-[4-(4-(1-ethoxycarbonylamino-1-cyanomethyl)-4-cyanopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide and Lawesson's reagent the compound was obtained in 58% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S@:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S:20][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)([OH:18])[C:14]([F:17])([F:15])[F:16])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Br)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
To a suspension of (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (11.5 g, 22.8 mmol) and sodium iodide (10.2 g, 68.1 mmol) in 180 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (16.0 mL, 113 mmol) in 30 mL of anhydrous acetone dropwise by syringe over 20 minutes. A greenish brown mixture was formed instantaneously. After 20 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The brown color disappeared and the crude was concentrated to remove most of the acetone solvent. The resulting material was diluted with 350 mL of water and extracted with three 600 mL portions of ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethyl-pentan-2-ol as a yellow oil (11.1 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:7]2[C:6]3[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:3]=[C:2]([CH3:1])[C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:28][CH:27]=1
Reactant: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: Fc1ccc(CBr)cc1
Product: CSc1c(CC(=O)OC(C)(C)C)cc(C)c2c3ccccc3n(Cc3ccc(F)cc3)c12
Yield: 91 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using tert-butyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and 4-fluorobenzyl bromide as starting materials, the title compound was obtained in a yield of 91% as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:13][CH:14]=1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(c2ccncc2)C1=O
Solvent: CO
Product: CC1(C)OC(c2ccc(O)cc2)=C(c2ccncc2)C1=O
Reaction time: 1 h
Yield: 99535.8 %

Procedure:
To a stirred solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (620 mg, 0.001 mmol) in MeOH (15 mL) was added Pd (OH)2 (120 mg, 0.85 mmol) at RT under an inert atmosphere. The reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(pyridin-4-yl)furan-3(2H)-one (280 mg, 60%) as a solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:17][CH:16]4[C:18]5([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]5)[CH:13]([CH2:14][CH2:15]4)[CH2:12][C:11]=3[CH:30]=2)=[N:4][CH:3]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36]([C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]4[CH2:17][CH:16]5[C:18]6([CH2:22][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[S:20](=[O:29])(=[O:28])[NH:19]6)[CH:13]([CH2:14][CH2:15]5)[CH2:12][C:11]=4[CH:30]=3)=[N:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(Br)s3)ccc2C1
Product: O=S1(=O)NC2(CN1CC(F)(F)F)C1CCC2Cc2cc(-c3ncc(-c4ccc(C(F)(F)F)cc4)s3)ccc2C1

Procedure:
Prepared using the bromide from Example 36 Step 2 and 4-trifluoromethylbenzeneboronic acid by the method described for Example 36 Step 3. MS (ES+) 588 ([MH]+).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:8][CH2:9][CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21])(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[CH:28]=[CH:27][C:26]([S:23]([NH:22][C@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[C:6]([OH:39])=[O:5])(=[O:25])=[O:24])=[CH:31][CH:30]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](CCCN1C(=O)c2ccccc2C1=O)NS(=O)(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 96.6 %

Procedure:
A solution of the title I compound, (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid t-butyl ester (0.96 g, 1.69 mmol) in TFA (10 mL, 130 mmol) is stirred at RT for 2.5 h. The solution is concentrated under reduced pressure to give a white solid which is triturated from 20 mL of diethyl ether, collected by filtration and dried to give 837 mg (97%) of (2R)-(4′-chlorobiphenyl-4-sulfonylamino)-5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid as a white solid: m.p. 179-181° C.; NMR(1:100 CD3OD/CDCl3) 1.65-1.86 (m, 4H), 3.63 (t, 3H, J=6.4), 3.93 (t, 3H, J=6.4), 7.39 (d, 2H, J=8.6), 7.47 (d, 2H, J=8.6), 7.60 (d, 2H, J=8.4), 7.65-7.68 (m, 2H), 7.76-7.79 (m, 2H), 7.86 (d, 2H, J=8.4); IR 1772, 1708, 1340, 1153; ESI-MS 511 (M−1), 513 (M++1).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]([CH3:23])[S:7]([C:10]1[CH:11]=[C:12]([C:20](O)=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]>>[CH3:5][N:6]([CH3:23])[S:7]([C:10]1[CH:11]=[C:12]([C:20]([Cl:3])=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CN(C)S(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Product: CN(C)S(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Yield: 100.1 %

Procedure:
190 g of thionyl chloride and 153 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with a condenser. The mixture was heated and then the excess thionyl chloride was distilled off. 163 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 160°-162° C.; yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[N:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc(N)cc2)o1)C(C)C
Reactant: O=C=Nc1ccccc1Cl
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)o1)C(C)C
Yield: 79 %

Procedure:
The title compound was synthesized analogous to Example 1, using 1-chloro-2-isocyanatobenzene and intermediate 1. Yield: 79%; 1HNMR (DMSO-d6, 300 MHz): δ 9.68 (s, 1H), 8.98 (d, 1H), 8.39 (s, 1H), 8.15 (dd, 1H), 7.82 (s, 1H), 7.78 (d, 2H), 7.63 (d, 2H), 7.48 (dd, 1H), 7.34 (m, 1H), 7.05 (m, 1H), 4.3, (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+) m/z 471 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O.C(OCC)C>C(Cl)Cl>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowly added at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) was slowly added reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h. After completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution followed by water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].Cl.[CH:18](OCC)=[O:19]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[CH:18][OH:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCOC(=O)Cc1cc(C)cc(C)c1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(=CO)c1cc(C)cc(C)c1
Reaction time: 12 h

Procedure:
10 ml of ethyl 2-(3,5-dimethylphenyl)acetate are dissolved in 80 ml of ethyl formate. 5 g of 50% NaH are added portionwise and then the mixture is stirred at AT for 12 hours. The mixture is poured onto a 1N HCl solution and then extraction is carried out with AcOEt. The organic phase is evaporated to produce the expected compound, used as is in the following stage.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:25])([F:24])[CH2:12][N:13]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl>C(O)C>[CH2:1]([O:8][CH2:9][CH2:10][C:11]([F:24])([F:25])[CH2:12][NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(F)(F)CCOCc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(F)(F)CCOCc1ccccc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
The compound N-(4-benzyloxy-2,2-difluorobutyl)phthalimide (8.97 g, 26 mM) and a 1M solution of hydrazine hydrate in ethanol (26 mL) are stirred under reflux. After a few minutes, a heavy precipitate is observed. Stirring and heating (bath temperature: 90°-100° C.) are continued overnight. Ethanol (220 mL) and concentrated HCl (18 mL) are added, and the mixture is refluxed for an additional 11/2 hour. After cooling (ice) the phthaloyl hydrazide is filtered, and the filtrate is evaporated. The residue is dissolved in water, filtered, and the solution is again evaporated. Residual water is removed by stripping with ethanol (twice) and CCl4 (twice). The residue is dissolved in a minimum amount of ethanol. Crystallization occurs upon the addition of water, which after chilling to 5° C. yields white crystals of 4-benzyloxy-2,2-difluorobutylamine as the hydrochloride salt: 5.16 g (79%).
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: [Li]c1ccccc1OC
Reactant: CON(C)C(=O)c1ccc(Cl)nc1Cl
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,6-Dichloro-N-methoxy-N-methyl-nicotinamide (503.3 mg, 2.141 mmol, Example 1) in anhydrous tetrahydrofuran (8 mL) was added a solution of freshly prepared 2-methoxyphenyl lithium (3-5 equiv, from above) and the reaction was stirred at −78° C. for 30-60 mins until the complete consumption of starting material. The resulting mixture was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with hexanes/ethyl acetate to give (2,6-Dichloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone as a light brown waxy solid (314.3 mg, 52% yield). HRMS, observed: 281.0023, Calcd for M+: 281.0010.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]([NH2:12])=[N:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]=[C:29]=[O:30].O>CN(C=O)C>[CH3:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[NH:28][C:29]([N:12]=[C:10]1[NH:9][C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11]1)=[O:30]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: NC1=NC(=O)C(c2ccccc2)(c2ccccc2)N1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)N=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A suspension of 6.95 g (0.0306 mole) of 5,5-diphenyl-2-amino-2-imidazoline-4-one in 300 ml of dry DMF is treated with 4.5 g (0.0306 mole) of 2,6-dimethylphenylisocyanate. The reaction mixture is stirred at 40° C. for two hours. It is then poured into cold water and the resulting solids are filtered off. To the crude product is added 30 ml of water with heating; acetone is added to the heated slurry until all solids go in solution (1.5 liters of acetone). The solution is then evaporated to a volume of 300 ml., chilled, and the resulting solids are filtered off to give 1-(2,6-dimethylphenyl)-3-(5,5-diphenyl-4-oxo-2-imidazolidinylidene) urea, the pure product; no m.p. up to 350° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cc(Cl)c(F)c(Br)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C(C)=O)cc(Cl)c(F)c1Br
Temperature: 60 °C
Yield: 39 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (5.3 g, 20 mmol), potassium carbonate (7.2 g, 52 mmol) and methyl iodide (2.7 mL, 44 mmol) in N,N-dimethylformamide (20 mL) was heated at 60° C. for 1 hour. The mixture was filtered and washed with ethyl acetate. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (39% yield). LCMS calculated for C9H8BrClFO2 (M+H)+: m/z=280.9, 282.9. found: 280.8, 282.8.