Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4]1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27]>CCOCC>[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27].[C:24]([OH:36])(=[O:35])[CH2:25][C:26]([CH2:31][C:32]([OH:34])=[O:33])([C:28]([OH:30])=[O:29])[OH:27].[O:11]([CH2:10][CH2:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CCCN(CCOc2ccccc2)C1
Reactant: C1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: c1ccc(OCCN2CCCC(CN3CCCCC3)C2)cc1

Procedure:
A mixture of 3-chloromethyl-1-(2-phenoxyethyl)piperidine (2.8 g) and piperidine (15 ml) was heated on a steam bath for 24 hours. The excess piperidine was removed under reduced pressure and the residue purified by azeotropic distillation with toluene. The residue was dissolved in ether/water and then basified to pH 14. The mixture was extracted with ether and the combined ether extracts yielded an oil which was dissolved in ether and acidified with ethereal citric acid to give a solid which was collected by filtration to give 1-(2-phenoxyethyl)-3-(piperidin-1-ylmethyl)piperidine dicitrate, m.p. 88°-89° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[NH:11][C:10]=2[CH2:21][CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]([CH3:25])[C:10]=2[CH2:21][CH3:22])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: CCc1[nH]c2ccc(F)cc2c(=O)c1-c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(-c2cc(F)cc(F)c2)c(=O)c2cc(F)ccc2n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3-(3,5-difluorophenyl)-2-ethyl-6-fluoroquinolin-4(1H)-one (280 mg, 0.9 mmol) in DMF (5 mL) was treated with NaH (60%, 1.5 eq, 55.3 mg). After 30 min, MeI (0.12 mL, 2.0 eq) was added dropwise and the reaction mixture was stirred at rt overnight before quenching with water. The reaction mixture was extracted with EtOAc (5 mL×2). The organic layers were combined washed with water, brine, dried, concd and purified by column chromatography on silica gel (EtOAc/hexane, 1/2) to give 3-(3,5-difluorophenyl)-2-ethyl-6-fluoro-1-methylquinolin-4(1H)-one as a white solid. Mass Spectrum (ESI) m/e=318 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=1.C([Sn](CCCC)(CCCC)[C:38]1[O:39][CH:40]=[CH:41][CH:42]=1)CCC>C1(C)C=CC=CC=1.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>[CH3:21][O:20][C:13]1[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=1[CH2:11][N:9]1[CH2:10][C:6]2[C:5]([F:23])=[C:4]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([NH2:28])=[O:27])[N:3]=[C:2]([C:38]3[O:39][CH:40]=[CH:41][CH:42]=3)[C:7]=2[C:8]1=[O:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(Cl)c3C2=O)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2Cc3c(F)c(N[C@H](CC(C)C)C(N)=O)nc(-c4ccco4)c3C2=O)c(OC)c1
Yield: 58 %

Procedure:
A solution of (R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)-4-methylpentanamide (150 mg, 0.323 mmol), tributyl(furan-2-yl)stannane (138 mg, 0.387 mmol), and tetrakis(triphenylphosphine)palladium(0) (373 mg, 0.323 mmol) in toluene (1 mL) was heated to 102° C. overnight. After removal of the solvent, the residue was diluted in MeOH/DCM (10 mL) and was purified via preparative HPLC eluting with water (0.05% TFA) and ACN (45-60% gradient, 0.035% TFA). The collected fractions were stripped to dryness via rotary evaporation to give the title compound (93.1 mg, 58%). [M+H] calc'd for C26H29FN4O5, 498; found 498.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15])[CH3:6])=[O:4].C(N=[C:23]=[O:24])CCC.C(Cl)(Cl)=O>N1(C2CCCCCCC2)CCCCCCN1.C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]=[C:23]=[O:24])(=[O:16])=[O:15])[CH3:6])=[O:4]
Reactant: COC(=O)C(C)Oc1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: COC(=O)C(C)Oc1ccccc1S(=O)(=O)N=C=O
Yield: 125.5 %

Procedure:
A mixture of 12.9 g of 2-(1-methoxycarbonylethoxy)benzenesulfonamide, 4.9 g of n-butylisocyanate and 0.1 g of diazabicyclooctane and 130 ml of xylene is refluxed for 30 minutes. Then 10 g of phosgene are passed into the solution at the same temperature over 90 minutes. Excess phosgene is expelled with nitrogen and the solution is then cooled and concentrated in vacuo, affording 17.7 g of 2-(1-methoxycarbonylethoxy)benzenesulfonyl isocyanate in the form of a brownish oil which can be further used without purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[ClH:30]>>[ClH:30].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=4[CH:29]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Product: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (100 mg) and 6N hydrochloric acid (10 ml) was stirred at 70° C. for 4 hours and concentrated under reduced pressure. To the residue was added 2-propanol, and the resulting solid was collected by filtration and washed with 2-propanol and diethylether to give yellow powder of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (89.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10]O)[CH:6]=[CH:7][C:8]=1[CH3:9].O=S(Cl)[Cl:14]>C(Cl)Cl>[Cl:14][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)ccc1C
Solvent: ClCCl
Product: COc1cc(CCl)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
To a solution of (3-methoxy-4-methylphenyl)methanol (2.0 g, 13.0 mmol) in dry DCM (20 mL) at 0° C., SOCl2 (3.1 g, 26.0 mmol) was added slowly. The resulting solution was stirred at room temperature for 0.5 h. The mixture was evaporated, and the residue was dissolved in DCM (20 mL). The mixture was washed with saturated NaHCO3 (3×10 mL), dried over Na2SO4 and evaporated to give the title compound as brown oil (2.1 g).
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccc(Br)cc1)c1ccccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
In a nitrogen stream, triethylsilane (1.84 mL, 11.55 mmol) and a boron trifluoride-diethylether complex (1.33 mL, 10.5 mmol) were added to a solution of (2-benzyloxyphenyl)-(4-bromophenyl)methanol (3.88 g, 10.5 mmol) in acetonitrile (19.5 mL) at −40° C. and the mixture was stirred at the same temperature for 0.5 hour. A saturated potassium carbonate aqueous solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (2.86 g, 77%).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2nncs2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nncs3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-[1,3,4]thiadiazol-2-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]([C:5]1[O:6][C:7]2[C:13]([S:14]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)(=[O:16])=[O:15])=[C:12]([Cl:18])[CH:11]=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1

Procedure:
Followed the general procedure described in Example 1c, 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride coupled with methyl-piperazine to give the desired product 3a, 600 mg (53%). LC-MS (m/z) 372.0 (M+H).
Reaction SMILES: [Mg].[Li+].[Cl-].CC(C[AlH]CC(C)C)C.Br[C:14]1[CH:15]=[C:16]([CH3:24])[C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[C:19]#[N:20].[Br:25][C:26]1[CH:27]=[C:28]([C:32]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[C:47]#[N:48])=[N:33]S(C(C)(C)C)=O)[CH:29]=[CH:30][CH:31]=1.Cl>C1COCC1.CO>[NH2:48][C:47]1[C:41]2[C:40](=[CH:45][CH:44]=[CH:43][C:42]=2[F:46])[C:32]([C:14]2[CH:15]=[C:16]([CH3:24])[C:17]([O:22][CH3:23])=[C:18]([CH:21]=2)[C:19]#[N:20])([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([Br:25])[CH:27]=2)[N:33]=1
Reactant: CC(C)(C)S(=O)N=C(c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1c(C)cc(Br)cc1C#N
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C)cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1C#N
Reaction time: 0.08 h
Yield: 32 %

Procedure:
Magnesium turnings (37.3 mg, 1.53 mmol) were stirred under Ar(g) for 10 min and LiCl 0.5M in THF (1.841 mL, 0.92 mmol) was added followed by DIBAL-H 1M in THF (6.14 μL, 6.14 μmol). The mixture was stirred for 5 min and 5-bromo-2-methoxy-3-methylbenzonitrile (194 mg, 0.86 mmol) in THF (1 mL) was added in one portion and stirring was continued for 2 h. The solution was transferred via canula to N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (250 mg, 0.61 mmol) in THF (3 mL) at rt and stirred o.n. MeOH (4 mL) was added and the mixture was treated with HCl in MeOH (1.473 mL, 1.84 mmol) o.n. The solvents were removed in vacuo, and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 2.5% (3.5 M ammonia in methanol) in dichloromethane afforded 0.088 g (32% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:25])[C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[Na+]>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:25])[C:15]=2[CH:14]=1)[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: CC1(C)CCC(C)(C)c2cc(CCl)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(COc3ccc(C=O)cc3O)ccc21
Yield: 46.9 %

Procedure:
3,4-Dihydroxybenzaldehyde (0.580 g., 4.20 mmol, 1 equiv.) is dissolved in 4.2 mL of acetone. 2-Chloromethyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) (18a) (1.00 g., 4.20 mmol, 1 equiv.), sodium iodide (0.020 g., 0.133 mmol, 0.03 equiv.), and potassium carbonate (0.580 g., 4.20 mmol, 1 equiv.) are added, and the mixture is heated to reflux for 19 hours. The mixture is poured into water, and extracted twice with ether, and once with EtOAc. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The crude material is chromatographed on silica gel using EtOAc/hexane as the eluent to afford 3-hydroxy-4-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl]methoxy benzaldehyde (41) (0.666 g., 1.97 mmol, 47%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.87 (s, 1H, CHO), 7.48-7.35 (m, 4H, ArH), 7.22 (dd, J= 2, 8 Hz, 1H, ArH), 7.09 (d, J=8 Hz, 1H, ArH), 5.14 (s, 2H, ArCH2O), 1.72 (s, 4H, CH2CH2), 1.32 (s, 6H, 2×CH3), 1.31 (s, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 191.00 (C=0), 151.20, 146.33, 145.79, 145.53, 132.11, 130.76, 127.17, 126.53, 125.51, 124.31, 114.28, 111.42, 71.60, 34.92, 34.26, 31.82; IR (KBr) 3342, 2962, 2932, 1682, 1608, 1582, 1512, 1278, 1112 cm-1 ; MS (DCI) m/e 339 (MH+), 201 (C15H21+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:27])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)=[CH:23][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc2ccc(Br)cc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 7-bromo-3-hydroxy-isoquinoline (7.02 g, 28.2 mmol) in dimethylformamide (75 mL) is treated with 4-bromomethylbenzoic acid tert-butyl ester (12.5 g, 36.7 mmol) and cesium carbonate (11.94 g, 36.7 mmol), then stirred overnight at room temperature. The dimethylformamide is evaporated in vacuo, the residue is diluted with ethyl acetate, washed with 1N HCl, the organic portion washed with brine, dried over MgSO4 and evaporated to dryness. The residue is triturated with hot hexanes/ethyl acetate, cooled to room temperature, and the solid is collected by filtration and dried to give the desired product.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[K].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)([O-:8])=[O:7]>CN(C)C=O>[Br:1][CH2:2][CH2:3][N:15]([C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1ccc(NS(=O)(=O)c2ccccc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(CCBr)S(=O)(=O)c2ccccc2)cc1
Temperature: 92.5 °C
Reaction time: 4 h

Procedure:
1,2-Dibromoethane (2.26 kg, 12 mol) mixed with 4 L of dimethylformamide was brought to 80° C. 1.264 kg (4 mol) of the potassium salt of N-(4-nitrophenyl)benzenesulfonamide (5) was added in portions and the mixture was stirred at 90-95° C. for 4 hours. The resulting mixture was filtered while hot and a KBr salt was formed, which was washed with dimethylformamide. The filtrate was poured onto 20 kg of ice in 20 kg of water. A yellow precipitate formed, which was filtered off by suction, reslurried three times in hot 1N sodium hydroxide, and then reslurried in water to neutral pH. The crude product (1.2 kg wet) obtained was recrystallized from 3 L of acetic acid. This mixture was filtered while boiling and the filtrate was cooled to 20° C. A white precipitate formed, which was filtered off by suction, washed with acetic acid and then with petroleum ether, and then dried under vacuum. 773 g product with a melting temperature of 168° C. were isolated.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH2:18][CH2:19][CH:20]=[CH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[O:9]1[CH2:21][CH:20]1[CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCc1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(CCC2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of m-chloroperbenzoic acid (43.5 g, 151 mmol) in chloroform (250 ml) was treated with 4-phenyl-1-butene (20 g, 151 mmol). The reaction was stirred for 1 hour at room temperature and washed with sodium bicarbonate, sodium sulfite, and saturated sodium chloride. The solution was dried over sodium sulfate and evaporated to dryness to afford 3,4-epoxybutylbenzene (100%).
Reaction SMILES: [CH:1](O)([CH3:3])[CH3:2].[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][C:9]=1[OH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>ClCCl>[CH3:5][O:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][C:9]=1[O:18][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: COC(=O)c1ccc(OC(C)=O)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)=O)cc1OC(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 78.6 %

Procedure:
Isopropanol (0.63 mL, 8.2 mmol) was added to a mixture of 4-Acetoxy-2-methoxy-benzoic acid methyl ester (Step 1, Example 299, 1.18 g, 5.6 mmol), Ph3P (1.84 g, 7.0 mmol), and dichloromethane (15 mL). Then DEAD (1.12 mL, 7.1 mmol) was added to the reaction. Reaction was stirred at room temperature for two days. Reaction solution was concentrated by rotary evaporation and the resulting residue was purified with silica gel prep plates and 1:5 EtOAc/Hexane as eluent. Obtained 1.11 g of 4-Acetoxy-2-isopropoxy-benzoic acid methyl ester in 79% yield.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25](CC(N)=O)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:36][O:35][C:33](=[O:34])[C:32]([N:25]1[CH2:26][CH:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[CH2:24]1)([CH3:38])[CH3:37]
Reactant: COC(=O)C(C)(C)Br
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)OCCc2sc(-c4ncnn4C(C)C)nc2-3)C1

Procedure:
The title compound was prepared by a similar procedure to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using methyl 2-bromoisobutyrate, cesium carbonate instead of potassium carbonate and DMF. The reaction was performed at 80° C. to give 2-{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester isolated as a white solid (147 mg, 60%). LCMS: RT=3.16 min, [M+H]+=468
Reaction SMILES: [NH2:1][C@@:2]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:7][O:6][C@@H:5]([CH:8]2[CH2:10][CH2:9]2)[CH2:4][C@H:3]1[C@@H:11]([OH:15])[CH2:12][O:13][CH3:14].C(OC[C@@H]1OC[C@@](N[C:48]([NH:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[S:49])(C2C=CC(F)=CC=2F)[C@H](CO)C1)C1C=CC=CC=1>>[CH:8]1([C@@H:5]2[O:6][CH2:7][C@@:2]([NH:1][C:48]([NH:50][C:51](=[O:58])[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)=[S:49])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C@H:3]([C@@H:11]([OH:15])[CH2:12][O:13][CH3:14])[CH2:4]2)[CH2:10][CH2:9]1
Reactant: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(N)c1ccc(F)cc1F
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Product: COC[C@H](O)[C@@H]1C[C@H](C2CC2)OC[C@@]1(NC(=S)NC(=O)c1ccccc1)c1ccc(F)cc1F

Procedure:
Conversion of rel-(1R)-1-[(2R,4R,5S)-5-amino-2-cyclopropyl-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]-2-methoxyethanol (C40) to the product was carried out via the method described for synthesis of N-{[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C7) in Preparation P1. In this case, purification was effected via silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane), affording the product as a solid. Yield: 0.55 g, 1.1 mmol, 43%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([OH:20])[CH3:19]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Product: CCOc1ccc2c(c1)CN(C(=O)OC(C)(C)C)C2

Procedure:
Prepared in analogy to Example A6(a) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and ethanol. Light brown solid. MS (m/e): 208.1 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([NH2:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(Cl)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 65.9 %

Procedure:
1-Chloro-5-methoxy-4-nitro-2-(trifluoromethyl)benzene (306 mg, 1.19 mmol) was dissolved in acetic acid (5 mL). Iron (436 mg, 7.78 mmol) was added and the mixture was heated under reflux for 1.5 hour. After cooling to room temperature, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure and the residue was taken up in EtOAc. The solution was washed with saturated NaHCO3 (aqueous) and brine, and then dried over MgSO4. Evaporation of the solvent in vacuo afforded an oily residue which was purified by flash chromatography on silica gel (cyclohexane-EtOAc, 7:3) to afford the title compound (177 mg, 66%) as a yellow oil (Rf 0.45, cyclohexane-EtOAc, 7:3). 1H-NMR (δ, ppm, DMSO-d6): 3.85 (s, 3H, CH3—O), 5.27 (bs, 2H, NH2), 7.02 (s, 2H, Harom). LC-MS (m/z): 226 (M+H, 100).