Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:27][CH:26]=3)[C:14]([CH:23]=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.CCOC(C)=O>[NH2:6][C:7]1[C:12]2=[C:13]([C:25]3[CH:26]=[CH:27][C:28]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][N:36]=4)=[O:33])=[CH:29][CH:30]=3)[C:14]([C:23]([CH:1]3[CH2:3][CH2:2]3)=[O:24])=[C:15]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Br[Mg]C1CC1
Reactant: Nc1ncnn2c(CN3CCOCC3)c(C=O)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ncnn2c(CN3CCOCC3)c(C(=O)C3CC3)c(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)cc3)c12
Yield: 10.8 %

Procedure:
Cyclopropyl magnesium bromide (7.40 mL, 3.70 mmol, 0.5 M in diethyl ether) was added dropwise to a stirring solution of Example 85 (200 mg, 0.37 mmol) in THF (10 mL). This was allowed to stir until the reaction was complete by HPLC (1 hour). Additional amounts of the grinard reagent were added as needed. The reaction was quenched with methanol and was worked up by adding 1 volume of saturated NH4Cl solution and 5 volumes of EtOAc. The organic layer was washed 2× with NH4Cl and 1× with sodium carbonate soln. The organic layer was dried over Na2SO4 and concentrated. The crude intermediate was dissolved in DMSO (3 nth) and treated with Dess-Martin periodinane (174.7 mg, 0.412 mmol). The reaction was allowed to stir until the reaction was complete by HPLC (2 hours). The reaction was diluted with EtOAc (200 mL) and washed 2× with both saturated NaHCO3 and 2M sodium thiosulfate solution. The organic layer was dried over Na2SO4 and concentrated to give a crude solid which was purified by HPLC (10-70% ACN/H2O) to give 26.3 mg of the above compound (0.04 mmol, 12.3% yield). 1H-NMR (DMSO-d6). δ 9.98 (s, 1H), 9.82 (s, 1H), 8.60 (d, J=5.4 Hz, 1H), 8.11 (s, 1H), 8.03 (s, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.45-7.41 (m, 3H), 4.08 (s, 2H), 3.55-3.52 (m, 4H), 2.46-2.43 (m, 4 H), 2.07-1.97 (m, 1H), 0.95-0.91 (m, 2H), 0.74-0.69 (m, 2H). MS [M+H]+=581; LCMS RT=2.68 min.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:63][CH2:62][CH2:61][CH2:60][N:59]([CH3:64])[CH3:58])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and N,N-dimethyl-1,3-propanediamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.49 (m, 3H) 1.53-1.87 (m., 9H) 2.13 (s, 6H) 2.25 (t, J=6.44 Hz, 2H) 3.29 (m, 2H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.26 Hz, 2H) 4.46 (m, 1H) 7.46 (d, J=8.0 Hz, 1H) 7.51 (s, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.08 Hz, 1H) 8.48 (br. s., 1H). [M+H] calculated for C27H37F2N7O3, 546. found 546.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23].Cl>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(F)c(C(=O)c2cccc(F)c2)c1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A total of 11.5 g of methyl 4-fluoro-3-(3-fluorobenzoyl)benzoate was dissolved in 40 ml of ethanol, and the reaction mixture was treated with 2.4 ml of hydrazine monohydrate with stirring at room temperature for 12 hours. The reaction mixture was treated with 2 N hydrochloric acid to be acidic and was extracted with two portions of ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was recrystallized from hexane-diisopropyl ether, to give 7.0 g of title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:27]1[CH2:28][CH2:29][CH:24]([N:21]2[CH2:22][CH2:23][CH:18]([CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:19][CH2:20]2)[CH2:25][CH:26]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Product: Fc1ccc2[nH]cc(C3=CCC(N4CCC(Cc5ccccc5)CC4)CC3)c2c1
Yield: 87.1 %

Procedure:
This compound was prepared from 5-fluoroindole and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone by the method described in Example 48 to give the product (87.1%, mp:72-74° C.). Calc'd for C26H29FN2.0.15C2H5OH: C, 79.83%; H, 7.72%; N, 7.04%. Found: C, 79.89%; H, 7.63%; N, 7.09%.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]21[O:4][CH2:1][CH2:2][O:3]2)=[O:20])[CH3:17]
Reactant: OCCO
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCCCC12OCCO2
Temperature: 25 °C
Yield: 74 %

Procedure:
Under an argon atmosphere, ethylene glycol (7.6 ml, 135.87 mmol) and para-toluenesulfonic acid (516 mg, 2.72 mmol) were added to a solution of (±)-2-(ethoxycarbonylmethyl)cyclohexanone (5.00 g, 27.17 mmol) in toluene (136 ml). The mixture was heated to reflux in a Dean Stark apparatus for 4 h and then allowed to cool to room temperature and quenched with sodium bicarbonate (5 g) and a saturated sodium bicarbonate solution (150 ml). The organic phase was separated from the aqueous phase which was extracted with ethyl acetate (3×100 ml). The combined organic phases were washed with a saturated sodium bicarbonate solution (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulphate and the solvent was evaporated under reduced pressure to give the crude product which was purified using flash column chromatography with hexane-ethyl acetate (9:1) to give (±)-6-(ethoxycarbonylmethyl)-1,4-dioxaspiro[4.5]decane (4.59 g, 74% yield) as a colourless oil. Rf 0.18 (hexane-ethyl acetate, 9:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:16])[C:10](=[CH2:15])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[CH2:24]([NH:31][CH2:15][CH:10]([CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[OH:16])[C:11]([O:13][CH3:14])=[O:12])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C(C(=O)OC)C(O)c1ccc(Cl)c(Cl)c1
Reactant: NCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of methyl 2-[(3,4-dichlorophenyl)(hydroxy)methyl]prop-2-enoate (13.6 g) and triethylamine (8.74 ml) in methanol (100 mL) was added benzylamine (6.84 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (12.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@H:8](O)[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:31]#[N:32])[CH:3]=1.C(N(S(F)(F)[F:39])CC)C.O.[Cl-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH2:7][C@@H:8]([F:39])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:31]#[N:32])[CH:3]=1
Reactant: CCOC(=O)[C@H](Cc1cccc(OC[C@@H](O)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Temperature: -68 °C
Reaction time: 96 h

Procedure:
65.3 g of ethyl (2S)-3-{3-[(2R)-3-(4-chloro-2-cyanophenoxy)-2-hydroxypropoxy]phenyl}-2-isopropoxypropionate was dissolved in 1.3L of dichloromethane, which was then cooled to −68° C. Then 54 mL of diethylaminosulfur trifluoride was added, followed by stirring at room temperature for 4 days. The reaction mixture was cooled with ice, to which water (1 L) and a saturated sodium chloride solution (1 L) were then added, followed by extraction with ethyl acetate (4 L). The organic layer was washed with the saturated sodium chloride solution (2 L) and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 33 g of ethyl (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate from a hexane-ethyl acetate (7:1→5:1)-eluted fraction. This compound was dissolved in 400 mL of ethanol, to which 107 mL of 2N sodium hydroxide aqueous solution was then added, followed by stirring the reaction mixture at room temperature for 2 hours. The reaction mixture was cooled with ice, to which water (500 mL) and a 5N hydrochloric acid aqueous solution (50 mL) were then added before further adding water (1 L), followed by extraction with ethyl acetate (2.5 L). The organic layer was washed with the saturated sodium chloride solution (1 L) and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under a reduced pressure. The residue was purified using silica gel column chromatography to obtain 27.6 g of the title compound in the form of colorless oily matter from a hexane-ethyl acetate (3:1→1:1)-eluted fraction.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24](O)=[O:25])=[O:21])[CH3:19])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:51]([O:58][C:59](=[O:63])[C@@H:60]([CH3:62])[NH:61][C:24](=[O:25])[C@@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[C@H:18]([CH3:19])[NH:17][P:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@@H](N)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h

Procedure:
Dibenzylphosphoryl-L-alanyl-L-proline (1.4 g, 3.2 m mole), HOBt (476 mg, 3.5 m mole) and D-alanine benzylester p-toluene sulfonic acid salt (1.3 g, 3.5 m mole) were dissolved in DMF (5 ml), and WSC (0.64 ml) was added thereto while cooling to -15° C. The reaction was carried out for 3 hours under cooling and then overnight at room temperature. To the reaction solution ethyl acetate (100 ml) was added and the mixture was washed with 1N hydrochloric acid, 5% sodium bicarbonate and water in order. The mixture was dried with anhydrous sodium sulfate and the thus obtained solution was distilled under reduced pressure to give an oily dibenzylphosphoryl-L-alanyl-L-prolyl-D-alanine benzylester material.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].[Na].Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1>C(O)C.CN(C)C=O>[CH:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:24]=[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]3[N:17]=2)=[CH:12][CH:11]=1)=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: BrCc1ccc(-c2nc3ccccn3n2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=Cc1ccc(-c2nc3ccccn3n2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
11.6 g of 2-nitropropane are introduced at about 30° C. into a solution of 2.3 g of sodium in 450 ml of absolute ethanol. The mixture is stirred for a further 1 hour and a solution of 28.8 g of 2-(p-bromomethyl-phenyl)-s-triazolo[1,5-a]pyridine (I) in 290 ml of dimethylformamide is now added. Subsequently, the reaction mixture is warmed to 50° C., then stirred for 20 hours without external warming and finally cooled to -10° C. The product which has precipitated is filtered off, washed with cold methanol and dried. This gives 19.3 g (86.5% of theory) of compound (II) in the form of a pale yellow powder with a melting point of 243° to 244° C. After recrystallising twice from dimethylformamide, 14.67 g (65.7% of theory) of small, virtually colourless, glossy needles with a melting point of 246° to 247° C. are obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH:2]=C.[O:16]=[O+][O-]>>[O:16]=[CH:2][CH2:1][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: C=CCOc1ccc(CCC(=O)O)cc1
Reactant: O=[O+][O-]
Product: O=CCOc1ccc(CCC(=O)O)cc1
Yield: 82 %

Procedure:
4-(2-Propenyloxy)benzenepropanoic acid (120 mg, 0.58 mmol) is treated with ozone by the procedure described in Example 2 to give 100 mg (82%) of 4-(2-oxoethoxy)benzenepropanoic acid as a white powder: m.p. 95°-100°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (KBr) 3400, 1740, 1720, 1610 cm-1 ; MS (CI low res) m/e 207, 191, 179, 165, 149.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:8].[Cl-].[NH4+]>O1CCCC1>[C:7]([C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])(=[O:8])[CH3:1]
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Methyl magnesium bromide in tetrahydrofuran (1M, 36.9 ml) was added into a solution of benzyl (2S)-2-(N-methoxy-N-methylcarbamoyl)-1-pyrrolidinecarboxylate (3.6 g) in tetrahydrofuran (36 ml) under ice-cooling. After being stirred for 2 hours at the same temperature, the reaction mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a mixture of hexane and ethyl acetate (1:1) as an eluent to give benzyl (2S)-2-acetyl-1-pyrrolidinecarboxylate (0.81 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]=1[F:24].[AlH4-].[Li+]>O1CCCC1>[F:24][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cccc(CO)c1F)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To 2-fluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoic acid methyl ester (24, 3.34 g, 8.85 mmol) in 71 mL of tetrahydrofuran, lithium tetrahydroaluminate (17.7 mL, 1.00 M in tetrahydrofuran, 17.7 mmol) was added under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature for 8 hours, followed by addition of 10 g of NaSO4.10H2O. After 12 hours, the reaction was filtered, the filtrate concentrated under vacuum and purified with silica gel column chromatography eluting with 40% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (25, 1.79 g, 58%). MS (ESI) [M−H+]−=348.4.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][CH:7]=1>C(#N)C>[S:1]([O:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCCc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)OCCc1ccccc1
Yield: 68 %

Procedure:
The title compound was obtained using the following procedure: The sulfamoyl chloride in acetonitrile solution prepared in (a) was reacted as in Example 12 with 12.2 g (0.1 mole) of β-phenethyl alcohol using 40.4 g (0.4 mole) triethylamine in 100 ml additional acetonitrile followed by using extracting, washing and concentration procedures of Example 12 through the first evaporation. The crude oily residue was purified by chromatography (10×80 cm glass column; 700 g silica gel; eluents methylene chloride followed by 10:1 methylene chloride/acetone). Fractions containing the title compound were combined and solvents evaporated under reduced pressure to give 13.6 g (68% yield) of title compound as light-yellow oil.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:20][CH3:21])O)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH3:21]
Reactant: CCc1cccc(F)c1C(O)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cccc(F)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-2-(tert-butyl-dimethyl-silanyl)-4-[(2-ethyl-6-fluoro-phenyl)-hydroxy-methyl]-imidazole-1-sulfonic acid dimethylamide, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100° C. for 16 h. White crystalline solid. MS (ISP): 205.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].O.[CH2:37]([OH:39])[CH3:38]>>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[N:16]=3)[CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][C:7]=1[O:39][CH2:37][CH3:38]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(-c2ccnc(Nc3cccc(Cl)c3)n2)ccn1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOc1cnn(-c2cc(-c3ccnc(Nc4cccc(Cl)c4)n3)ccn2)c(=O)c1Cl
Yield: 35 %

Procedure:
To a suspension of 4,5-Dichloro-2-{4-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-pyridin-2-yl}-2H-pyridazin-3-one (0.3 g) in ethanol (10 mL) was added of 0.220 mg of potassium carbonate. The mixture was heated to reflux for 4 h. The suspension was poured into water (50 mL) and extracted with ethyl acetate (2×100 mL). The organic phase were combined, dried over MgSO4, and concentrated. Flash silica chromatography, eluting with ethyl acetate-hexane (9:1), afforded the title compound as a solid (0.130 g, 35%). Mp 196–198° C., 1H NMR (CDCl3) 8.80 (1H, d, 3 Hz), 8.60 (1H, d, 6 (1H, s), 8.02 (2H, d, m), 7.93 (1H, s), 7.46 (1H, dd, 6 Hz, 3 Hz), 7.31 (1H,m), 7.29 (1H, d 3 Hz), 7.28 (1H, s), 4.43 (2H, q, 6 Hz), 1.56 (3H, t, 6 Hz).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.Cl.CC(O)C>C(Cl)Cl>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]([CH3:38])[C:34]([F:36])([F:37])[F:35])=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CC(Nc1ncc2c(n1)CN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(Nc1ncc2c(n1)CN(C(=O)N[C@H](CO)c1ccc(Cl)c(Cl)c1)CC2)C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 302 (0.160 g, 0.270 mmol) and DCM (5 mL) at RT was added 6M HCl in IPA (0.450 mL, 2.70 mmol) and the reaction was stirred for 1 h. The reaction was poured into satd. aq. Na2CO3, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:20 to 500:30) to afford 0.010 g (7.74%) of I-76: MS m/z (APCI-pos) M+1=478.
Reaction SMILES: [CH:1]1([C:4](=O)[CH:5]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=O)[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH:1]1([C:4]2[S:33][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[N:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1
Reactant: COC(=O)C(NC(=O)c1cccc(C(F)(F)F)c1)C(=O)C1CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2cccc(C(F)(F)F)c2)sc1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution (12 mL) of the compound (4.0 g, 12 mmol) obtained in Example 72b in tetrahydrofuran was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (4.9 g, 12 mmol), and the mixture was stirred at 80° C. overnight. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give the title compound (3.4 g, 86%) as a colorless solid.