Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1>CO>[OH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH:2][OH:3])=[NH:10])=[CH:7][CH:6]=1
Reactant: NO
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: N=C(NO)c1ccc(O)cc1
Yield: 69.4 %

Procedure:
To dry methanol (285 mL) is carefully added K-tert.-butylate (28.28 g, 252 mmol) followed by hydroxylamine hydrochloride (15.0 g, 216 mmol). The suspension is stirred for 30 min before 4-hydroxybenzonitrile (8.58 g, 72 mmol) is added. The mixture is refluxed for 40 h, the solvent is evaporated and the residue is acidified by adding 2 N aq. HCl. The solution is extracted twice with DCM (100 mL). The aq. layer is basified by adding solid NaHCO3. The product precipitates, is filtered off, washed with water and dried to give 4,N-dihydroxy-benzamidine (7.6 g) as a brownish solid; 1H NMR (D6-DMSO): δ 9.57 (s, 1H), 9.33 (s, 1H), 7.48-7.42 (m, 2H), 6.74-6.68 (m, 2H), 5.62 (s, 2H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(C)=O.C1([O:14][C:15](=O)[NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:34](=[O:36])[NH2:35])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[C:39]([F:42])([F:41])[F:40])C=CC=CC=1.O>C(OCC)(=O)C>[C:34]([C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:37][CH3:38])[N:27]=[CH:26][CH:25]=[C:24]2[O:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]([NH:3][CH2:1][CH3:2])=[O:14])=[C:18]([C:39]([F:41])([F:40])[F:42])[CH:19]=1)(=[O:36])[NH2:35]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C(F)(F)F)c3)c2cc1C(N)=O
Reactant: CCN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Ethylamine 2N tetrahydrofuran solution (0.10 ml) was added to dimethylsulfoxide (0.5 ml), and then (4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl) carbamic acid phenyl ester (25 mg) was dissolved therein and the mixture was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (5.0 mg).
Reaction SMILES: [S:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[CH2:25][CH2:24][CH2:23][C:22](=[O:26])[CH:21]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:26])[CH2:23][CH2:24][CH2:25][C:20]=3[NH:19][C:5]3[CH2:6][S:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1CSCC(=O)C1
Reactant: NC1=CC(=O)CCC1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CSCC1=O)N2
Temperature: 80 °C
Yield: 31.8 %

Procedure:
A mixture of thiopyran-3,5-dione (Fehnel, E. A., J. Amer. Chem. Soc., (1955), 77, 4241-4244) (0.12 g, 1.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.20 g, 1.0 mmol), 3-amino-2-cyclohexene-1-one (0.11 g, 1.0 mmol) and ethanol (5 mL) was heated to 80° C. in a sealed tube for 60 hours and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol and dried for 16 hours under high vacuum to provide the title compound (0.13 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=C=O)/[CH:16]=[CH:17]/[C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)C1C=CC=CC=1.F[C:30](F)(F)C(O)=O.[H][H]>[Pd].[C].C(O)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH3:30])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C=C(/C=C/c1ccc(C(=O)[O-])cc1)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCCc2ccccc2O)cc1

Procedure:
A mixture of 4-[3-(2-benzyloxyphenyl)-3-carbonyl-1(E)-propenyl]benzoate (35 g), 10% Pd-carbon (7 g), acetic acid (350 mil) and trifluoroacetic acid (7 ml) was warmed at 30° C. under 10 atm. of hydrogen for 18 hours, filtered and the filtrates evaporated. The residue was triturated with hexane and dried to give methyl 4-(3-(2-hydroxyphenyl)propyl]benzoate (26 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23](=[CH:25][C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:24]>C(O)C>[CH3:20][C:19]1[NH:22][C:23]([CH3:24])=[C:25]([C:26](=[O:32])[CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(N)=CC(=O)CCC(C)C
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CCC(C)C)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 35 mg (0.227 mmol) of 2-amino-7-methyloct-2-en-4-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 45.3 mg (61% of theory) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12].[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C=O)C>[C:13]1(=[O:23])[N:17]([CH2:2][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=2[O:11][CH3:12])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: COc1cc(C#N)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C#N)ccc1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
24.4 g (108 mol) of 4-bromomethyl-3-methoxybenzonitrile dissolved in 125 ml of DMF and 20.0 g of potassium phthalimide were stirred at RT for 24 h and then at 50° C. for 1 h. The mixture was poured into water, whereupon the product precipitated as solid. 21.5 g (68%) of the product were obtained.
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[S:11](Cl)(=[O:13])=[O:12].[N:15]1([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:33])([F:32])[F:31])=[N:28][N:29]=3)[N:26]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:18]1[CH2:17][CH2:16][N:15]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([C:30]([F:31])([F:32])[F:33])=[N:28][N:29]=3)[N:26]=2)[CH2:20][CH2:19]1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Solvent: c1ccncc1
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
Naphthalene-2-sulfonyl chloride (175 mg, 0.77 mmol) was added to 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (150 mg, 0.55 mmol) in pyridine (2 mL). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was evaporated to remove the pyridine. The crude product was purified by preparative HPLC (Phenomenex Gemini C18 110A (axia) column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-(naphthalen-2-ylsulfonyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (168 mg, 66%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]([OH:20])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:44][C:45]1[N:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=[C:10]([C:18]([NH:52][CH2:51][C:48]3[CH:49]=[N:50][C:45]([CH3:44])=[CH:46][CH:47]=3)=[O:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(S(C)(=O)=O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-(methylsulfonyl)biphenyl-3-carboxylic acid (40 mg, 0.14 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (53 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (21 mg, 0.14 mmol), and CH2Cl2 (3 mL) were added (6-methylpyridin-3-yl)methanamine (25 mg, 0.21 mmol), and N,N-diisopropylethylamine (48 μL, 0.28 mmol). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by preparative HPLC (100×20.2 mm, C18 column; 30-80% CH3CN-water[10 mM Et2NH]) to afford a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([CH3:19])[CH:11]=1.C(=O)([O-])[O-].[Tl+2]>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=2[CH3:19])[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: Cc1cc(F)ccc1B(O)O
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: [Tl+2]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(F)ccc1-c1cccc(Br)n1
Yield: 74.4 %

Procedure:
In a 100 ml round-bottomed flask, 7.92 g (33.4 mmol) of 2,6-dibromopyridine was dissolved in 50 ml of anhydrous toluene forming a clear, colorless solution. 4-fluoro-2-methylbenzene boronic acid (5.09 g, 33.1 mmol) produced in step A was added forming a white suspension. Thallium carbonate (17.45 g, 37.2 mmol) was added followed by a catalytic amount (150 mg) of Pd(PPh3)4. The mixture was heated to reflux overnight, cooled, and filtered over a pad of silica gel. The silica was washed with CH2Cl2 and the filtrate was evaporated to afford a white solid. The solid was dissolved in a minimal amount of 50% CH2Cl2/hexane and chromatographed on a short column of silica gel using 30% CH2Cl2/hexane to afford 6.55 g (74%) of the 2-bromo-6-(4-fluoro-2-methylphenyl)pyridine as a white solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[N:3]1([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ccnc1
Yield: 57.3 %

Procedure:
A suspension of 16.0 g (0.4 mol) of NaH.oil (60%) was washed with hexane to remove the oil and then resuspended in 400 mL of THF. This was then treated dropwise with a solution of 27.23 g (0.4 mol) of imidazole in 150 mL of THF and then refluxed for 1 hour. This was then treated dropwise with a solution of 72.4 g (0.4 mol) of ethyl 2-bromopropanoate in 100 mL of THF and the mixture heated at reflux for 2.5 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in Et2O and washed with H2O, then saturated NaCl. Drying over MgSO4 and treatment with charcoal gave the crude product. This was triturated with pentane and the pentane removed under reduced pressure to give 38.56 g (57.3% yield) of the product as an oil. The structure was confirmed by NMR and mass spectroscopy. MS m/z 169 (M+H+).
Reaction SMILES: F.F.F.[CH2:4](N(CC)CC)C.C(N(CC)CC)C.[Si]([O:35][CH:36](C)[C@H:37]1[O:41][C@@H:40]([N:42]2[CH:49]=[CH:48][C:46](=[O:47])[NH:45][C:43]2=[O:44])[C@H:39]([O:50][CH2:51][CH2:52][O:53][N:54]([CH3:56])[CH3:55])[C@@H:38]1[OH:57])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.C(Cl)Cl>[CH3:56][N:54]([CH3:55])[O:53][CH2:52][CH2:51][O:50][C@@H:39]1[C@H:38]([OH:57])[C@@H:37]([CH2:36][OH:35])[O:41][C@H:40]1[N:42]1[CH:49]=[C:48]([CH3:4])[C:46](=[O:47])[NH:45][C:43]1=[O:44]
Reactant: CCN(CC)CC
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OCCON(C)C)[C@@H]1O
Agent: F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCON(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.4 %

Procedure:
Triethylamine trihydrof luoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and triethylamine (1.67 mL, 12 mmol, dry, kept over KOH). This mixture of triethylamine-2HF was then added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5′-methyluridine (1.40 g, 2.4 mmol) and stirred at room temperature for 24 hrs. Reaction was monitored by TLC (5% MeOH in CH2Cl2). Solvent was removed under vacuum and the residue placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)(=O)OCC)C.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:23].[CH2:27]([O:29][C:30]([CH:32]1[CH:34]([CH:35]=O)[C:33]1([CH3:38])[CH3:37])=[O:31])[CH3:28]>O1CCCC1.CCCCCC.O>[CH2:27]([O:29][C:30]([CH:32]1[CH:34]([CH:35]=[C:9]([Cl:23])[C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:33]1([CH3:38])[CH3:37])=[O:31])[CH3:28]
Reactant: CCOP(=O)(Cc1ccc(Cl)cc1)OCC
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1C(C=C(Cl)c2ccc(Cl)cc2)C1(C)C
Temperature: -70 °C
Yield: 54.3 %

Procedure:
26.3 g (0.1 mol) of 4-chlorobenzyl-phosphonic acid diethyl ester were dissolved in 400 ml of absolute tetrahydrofuran and the solution was cooled to -70° C. 0.11 mol of n-butyl-lithium (as a 15% strength solution in hexane) were added dropwise under a counter-current of nitrogen and while stirring well, and the reaction mixture was then stirred for a further 15 minutes at -70° C. Thereafter, 15.4 g (0.1 mol) of carbon tetrachloride were added dropwise at -70° C., still under nitrogen; in the course thereof, the reaction mixture assumed a red-brown color. After stirring for a further 15 minutes, 18.6 g (0.1 mol) of 2,2-dimethyl-3-formyl-cyclopropanecarboxylic acid ethyl ester were added at -65° C. The reaction mixture was then allowed to come to room temperature and was stirred for a further 3 hours at 25° C. The reaction batch was then poured into 2 liters of water and extracted with 600 ml of ether. The ether phase was dried over sodium sulphate, the solvent was stripped off in vacuo and the oily residue was distilled at 150°-155° C./2 mm Hg. 2,2-Dimethyl-3-(2-chloro-2-p-chlorophenyl-vinyl)-cyclopropanecarboxylic acid ethyl ester was obtained in 54.3% yield.
Reaction SMILES: Br[C:2]1[C:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(N)CN.[Li]CCCC.C[O:33]B(OC)OC.OO.Cl>C1COCC1.O>[CH2:13]([C:3]1[C:2]([OH:33])=[C:7]([O:8][CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: O
Solvent: NCCN
Solvent: C1CCOC1
Product: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution at −5° C. containing 500 mg (1.34 mmol) of 5-bromo-4-decyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 10 mL of anhydrous THF were added 202 μL (1.34 mmol) of N,N,N,N-tretamethyl ethylenediamine followed by 2.09 mL (3.35 mmol) of 1.6 M solution of n-BuLi in hexanes. The reaction mixture was stirred at −5° C. for 20 min. Then to the mixture were added 440 μL (4.02 mmol) of trimethoxy boron and the reaction mixture was stirred at 23° C. for 1 h. Then to reaction mixture were added 3.46 mL of 30% aq H2O2. The reaction mixture was then stirred for 30 min and poured into 100 mL of water. The mixture was neutralized with diluted aq. HCl and extracted with two 100-mL portions of ethyl acetate. The combined organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as white solid: yield 111 mg (27%); mp: 59-60° C.; silica gel TLC Rf=0.60 (4:1 hexanes-ethyl acetate); 1H-NMR (methanol-d4) δ 0.87 (t, 3H, J=6.4 Hz), 1.33-1.24 (br m, 14H), 1.62 (quint, 2H, J=7.2 Hz), 2.58 (dd, 2H, J=7.6, 7.6 Hz), 3.09 (s, 6H) and 3.91 (s, 3H); 13C NMR (methanol-d4) δ 13.05, 22.32, 27.62, 29.05, 29.15, 29.17, 29.29, 29.31, 30.58, 31.67, 36.32, 36.32, 52.23, 126.96, 155.92, 155.94 and 159.48.
Reaction SMILES: [CH2:1]([Sn:11]([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])(C1C=CSC=1)[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Br:32]Br>>[CH2:1]([Sn:11]([Br:32])([CH2:22][C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH3:24])[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C[Sn](CC(C)(C)c1ccccc1)(c1ccsc1)c1ccsc1)c1ccccc1
Product: CC(C)(C[Sn](Br)(CC(C)(C)c1ccccc1)c1ccsc1)c1ccccc1

Procedure:
In substantial accordance with the procedure described in Example 1(2), dineophyl-di(3-thienyl)tin (80 g, 0.145 mol) obtained above was reacted with bromine to give crude dineophyl-3-thienyltin bromide, which was then reacted with sodium fluoride. The resulting product was recrystallized from n-hexane to provide 21.5 g of dineophyl-3-thienyltin fluoride as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])=[CH:12][C:13]=1[C:14]#[C:15][CH2:16][C:17]([OH:40])([C:36]([F:39])([F:38])[F:37])[CH2:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](=[O:35])(=[O:34])[N:29]=CN(C)C)([CH3:21])[CH3:20])(C)(C)C.C1CCN2C(=NCCC2)CC1.O>CO>[CH2:44]([S:41]([C:11]1[CH:12]=[C:13]2[CH:14]=[C:15]([CH2:16][C:17]([OH:40])([C:36]([F:39])([F:37])[F:38])[CH2:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([NH2:29])(=[O:35])=[O:34])([CH3:21])[CH3:20])[NH:7][C:8]2=[CH:9][N:10]=1)(=[O:42])=[O:43])[CH3:45]
Reactant: CCS(=O)(=O)c1cc(C#CCC(O)(CC(C)(C)c2ccccc2S(=O)(=O)N=CN(C)C)C(F)(F)F)c(NC(=O)OC(C)(C)C)cn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: CCS(=O)(=O)c1cc2cc(CC(O)(CC(C)(C)c3ccccc3S(N)(=O)=O)C(F)(F)F)[nH]c2cn1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 48.2 %

Procedure:
To a vial was added {4-[6-(2-{[1-dimethylaminomethylidene]sulfamoyl}phenyl)-4-hydroxy-6-methyl-4-trifluoromethylhept-1-ynyl]-6-ethanesulfonylpyridin-3-yl}carbamic acid tert-butyl ester (48 mg, 0.07 mmol) in 3 mL of methanol, followed by the addition of DBU (106 mg, 0.7 mmol). The reaction mixture was stirred at 70° C. for 90 minutes. To the reaction was added 0.5 mL of water, and the reaction mixture was stirred at 70° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The crude mixture was purified by flash chromatography. The column was eluted with 0-5% MeOH/CH2Cl2 to afford 18 mg (48%) of 2-[3-(5-ethanesulfonyl-1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-4,4,4-trifluoro-3-hydroxy-1,1-dimethylbutyl]benzenesulfonamide. MS (ES+) m/z 534 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([NH:27][C@@H:28]([CH3:32])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH:11][C:29](=[O:30])[C@@H:28]([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH3:32])[C:5]=1[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1c(F)ccc(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (2.0 g, 7.7 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.6 g, 8.45 mmol), HOAt (760 mg, 8.45 mmol), 4-methylmorpholine (1.86 mL, 16.9 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g, 8.45 mmol) in DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford 3-((S)-2-tertbutoxycarbonylaminopropionylamino)-6-fluoro-2-phenylaminobenzoic acid methyl ester. LCMS (Method B): RT 3.65 min [M+H]+ 432.3.
Reaction SMILES: [NH2:1][C@H:2]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33](=[O:41])[N:34]([CH2:38][CH2:39][OH:40])[CH2:35][CH2:36][OH:37])=[CH:27][CH:26]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4].C(N(CC)CC)C.[CH3:49][Si:50](Cl)([CH3:52])[CH3:51].C(OCC)(=O)C>O1CCCC1>[NH2:1][C@H:2]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33](=[O:41])[N:34]([CH2:38][CH2:39][O:40][Si:50]([CH3:52])([CH3:51])[CH3:49])[CH2:35][CH2:36][O:37][Si:50]([CH3:52])([CH3:51])[CH3:49])=[CH:29][CH:30]=1)[C:3]([NH:5][C@H:6]([C:15]1[NH:19][C:18]2[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:17]=2[N:16]=1)[C@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:4]
Reactant: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO)CCO)cc1)c1nc2ccc(I)cc2[nH]1
Reactant: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OCC(=O)N(CCO[Si](C)(C)C)CCO[Si](C)(C)C)cc1)c1nc2ccc(I)cc2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
(R)-2-Amino-2-(4-{[bis-(2-hyd roxy-ethyl )-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide (170 mg, 0.253 mmol) was dissolved in dry tetrahydrofuran (3.4 mL) and cooled in an ice bath. To this solution was added triethylamine (176.3 μL, 1.265 mmol) followed by trimethylsilyl chloride (132 μL, 1.012 mmol). After 0.5 hours another 2.5 equivalents of triethylamine (88 μL, 0.63 mmol) and 2 equivalents of trimethylsilyl chloride (66 μL, 0.506 mmol) were added. The reaction mixture was stirred at 0° C. for an additional 1.5 hours then the reaction mixture was poured into ethyl acetate (40 mL) and washed with brine (3×25 mL). The combine aqueous washes were then extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give (R)-2-amino-2-(4-{[bis-(2-trimethylsilanyloxy-ethyl)-carbamoyl]-methoxy}-phenyl)-N-[(1S,2S)-1-(6-iodo-1H-benzoimidazol-2-yl)-2-phenyl-propyl]-acetamide (190 mg, 92%).