Azzindani/Open_Reaction_Data huggingface dataset:
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[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].[CH3:22][C:23](C)([O-:25])[CH3:24].[K+].C(C1OC1)Br>CC(N(C)C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][CH:23]1[CH2:24][O:25]1
Reactant: Oc1ccccc1CCCCc1ccc2ccccc2c1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(OCC2CO2)c(CCCCc2ccc3ccccc3c2)c1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(a), 300 mg of 2-[4-(2-naphthyl)butyl]phenol (prepared as described in Preparation 15), 122 mg of potassium t-butoxide and 301 mg of epibromohydrin were reacted in 15 ml of dimethylacetamide. The crude product, extracted as described in Example 1(a), was purified as described in Example 1(a), to give 303 mg (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [S-]C#N.[NH4+].Cl[C:6]1[C:11]([C:12]([N:14]=[C:15]=[S:16])=[O:13])=[CH:10][N:9]=[CH:8][CH:7]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([NH:22][CH3:23])=[CH:20][CH:19]=1>CC(C)=O.C1COCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([N:22]([C:15]2[S:16][C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[C:12](=[O:13])[N:14]=2)[CH3:23])=[CH:20][CH:19]=1
Reactant: O=C(N=C=S)c1cnccc1Cl
Reactant: CNc1ccc(Cl)cc1
Agent: N#C[S-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(c1ccc(Cl)cc1)c1nc(=O)c2cnccc2s1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1.416 g (8.99 mmol) of 4-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure to obtain 4-chloronicotinoyl chloride. The compound thus obtained was then suspended in a mixture of 10 ml of acetone and 10 ml of THF. The suspension thus obtained was then added dropwise to a solution of 753 mg of ammonium thiocyanate in 15 ml of acetone with stirring in 5 minutes. After the termination of dropwise addition, the reaction mixture was heated to a temperature of 40° C. with stirring for 6 minutes to obtain a mixture containing 4-chloronicotinoyl isothiocyanate. To the mixture thus obtained was then added dropwise a solution of 1.55 g of 4-chloro-N-methylaniline in 10 ml of acetone with stirring in 5 minutes. The reaction mixture was stirred at room temperature for 17 hours, concentrated to half the initial volume under reduced pressure, and then poured into about 500 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The resulting crude product was purified through silica gel column chromatography (eluant: CHCl3 +1 to 3% methanol), and then recrystallized from ethanol to obtain 717 mg of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3,4-e]-1,3-thiazin-4-one.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.ClC(N(C)C)=C(C)C.[C:27]([O:36][CH3:37])(=[O:35])[C:28]1[C:29](=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:30].N1C=CC=CC=1>C(Cl)Cl.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[C:27]([O:36][CH3:37])=[O:35])=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Reactant: COC(=O)c1ccccc1N
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To a suspension of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 500 mg, 2.0 mmol) in CH2Cl2 (10 mL) at room temperature is added 1-chloro-N,N,2-trimethylpropenylamine (0.98 mL, 7.2 mmol). After stirring for 3 h, methyl anthranilate (1.3 mL, 10.2 mmol) and pyridine (0.66 mL, 8.2 mmol) are added. The mixture is stirred for another 16 h at room temperature. Water (100 mL) is added and the mixture is extracted with EtOAc (3×100 mL). The organic layers are combined, dried and evaporated. Methanol (50 mL) is added to the oily residue, and a white solid is formed. The solid is filtered to afford the title compound (503 mg, 65%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[H-].[Na+].Cl[C:34]([O:36][CH3:37])=[O:35]>O1CCCC1.O.CN(C)C=O>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([CH:10]2[C:9]3[C:8](=[O:20])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)[C:2](=[O:1])[N:11]2[C:34]([O:36][CH3:37])=[O:35])=[CH:19][CH:18]=1)#[N:17]
Reactant: COC(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 60 mg, 0.146 mmol) in tetrahydrofuran (0.8 mL) is added to a suspension of sodium hydride (60% in mineral oil, 7 mg, 0.17 mmol) in tetrahydrofuran (0.5 mL). After 20 min methyl chloroformate (11 μL, 0.15 mmol) is added and the mixture is stirred at room temperature over night. Another portion of sodium hydride (60% in mineral oil, 3 mg, 0.07 mmol) is added. After 2 h, the mixture is diluted with water and N,N-dimethylformamide and then purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 8 mg; ESI mass spectrum [M+H]+=470, Retention time HPLC: 1.14 min (V011_S01).
Reaction SMILES: O=C1NC(=O)NC2NN=CC1=2.[CH2:12]([N:14]1[C:19]2[N:20]([CH3:23])[N:21]=[CH:22][C:18]=2[C:17](=[O:24])[NH:16][C:15]1=[O:25])[CH3:13].[Br:26][CH2:27][CH2:28][CH2:29]Br>>[Br:26][CH2:27][CH2:28][CH2:29][N:16]1[C:17](=[O:24])[C:18]2[CH:22]=[N:21][N:20]([CH3:23])[C:19]=2[N:14]([CH2:12][CH3:13])[C:15]1=[O:25]
Reactant: CCn1c(=O)[nH]c(=O)c2cnn(C)c21
Reactant: BrCCCBr
Agent: O=c1[nH]c(=O)c2cn[nH]c2[nH]1
Product: CCn1c(=O)n(CCCBr)c(=O)c2cnn(C)c21

Procedure:
Provided one of the residues R1 or R2 is an alkylcarbonylalkyl group, profitably one can proceed in the way, that the corresponding 4,5,6,7-tetrahydro-4,6-dioxo-pyrazolo-[3,4-d]-pyrimidine is alkylated with a ω-ω'-dibromalkane to ω-alkyl derivative which is treated with acetoaceticester and the reaction product is subjected to a ketone decomposition reaction. For example by such a reaction with the 7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-1H-pyrazolo-[3,4-d]-pyrimidine with 1,3-dibromopropane, the 5-(3-bromopropyl)-7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-1H-pyrazolo-[3,4-d]-pyrimidine is obtained, which upon acetoaceticester condensation and subsequent ketone decomposition yields the 7-ethyl-4,5,6,7-tetrahydro-1-methyl-4,6-dioxo-5-(5-oxo-n-hexyl)-1H-pyrazolo-[3,4-d]-pyrimidine. The alkylcarbonyalky rest can also be introduced by direct alkylation reaction of the appropriate 4,5,6,7-tetrahydro-4,6-dioxo-pyrazolopyrimidine, preferably as a sodium salt, with an alkylcarbonylalkylhologenide, preferably a chloride or a bromide. For example a 5-oxo-n-hexyl group can be introduce by using 1-bromohexanone-5.
Reaction SMILES: [C:1]1([C:7]([OH:23])([CH2:9][CH2:10][NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:8][C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:23][C:32](=[O:34])[N:11]([C:12]2[S:13][CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: CC(O)(CCNc1nc(-c2ccccc2)cs1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1(c2ccccc2)CCN(c2nc(-c3ccccc3)cs2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.1 %

Procedure:
To a solution of 2-phenyl-4-(4-phenylthiazol-2-ylamino)butan-2-ol (50 mg, 0.15 mmol) and Et3N (80 mg, 0.75 mmol) in CH2CH2 (5 mL) was added triphosgene (15 mg, 0.05 mmol) at 0° C. Then, the mixture was stirred at rt overnight. The reaction solution was concentrated to give an oil, which was purified by column chromatography (1:2 petroleum ether/EtOAc) to afford 6-methyl-6-phenyl-3-(4-phenylthiazol-2-yl)-1,3-oxazinan-2-one (20 mg, 37%). LC-MS Method 3, tR=1.446 min, m/z=351. 1H NMR (CDCl3, 400 Hz): 1.80 (s, 3H), 2.45 (m, 1H), 2.65 b (m, 1H), 3.70 (m, 1H), 4.42 (m, 1H), 7.18 (s, 1H), 7.20-7.40 (m, 8H), 7.80 (d, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH2:32][CH2:33][CH2:34]O)([O-:22])=[O:21].C(Br)(Br)(Br)[Br:37]>C(#N)C>[Br:37][CH2:34][CH2:33][CH2:32][C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[NH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCBr)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of triphenylphosphine (6.70 g, 0.025 mol) in 80 mL of acetonitrile was added a solution of 5-nitro-3-(3-hydroxypropyl)indole (18) (4.30 g, 0.020 mol) in 75 mL of acetonitrile, followed by a solution of CBr4 (9.00 g, 0.027 mol) in 25 mL of acetonitrile, at 0° C. under Ar. The mixture was stirred at room temperature for 3 h and then it was evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane, 1:9 then 1:4) to give the title compound (4.60 g, 84%) as a solid, mp 92°-95° C.: IR (neat) 3420, 1330 cm-1 ; 1H NMR (CDCl3, 200 MHz) δ 8.59 (d, J=2.1 Hz, 1H), 8.40 (br s, 1H), 8.13 (dd, J=9.0, 2.2 Hz, 1H), 7.40 (d, J=9.1 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 3.45 (t, J=6.4 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.26 (m, 2H).
Reaction SMILES: O[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28].Cl>O.C(O)C>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH:32][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[CH:3][CH:4]=1)[CH3:28]
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: CCN(CC)CCN
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCN(CC)CCNc1ccc(NCCN(CC)CC)c2c1C(=O)c1ccccc1C2=O
Temperature: 90 °C
Yield: 7.6 %

Procedure:
A mixture of 5 g (0.021 mol) of 1,4-dihydroxyanthracene-9,10-dione and 2 g (0.014 mol) of sodium dithionite in 20 ml water is stirred whilst heating under nitrogen at 90° C. until the mixture turns from orange to brown indicating the presence of 2,3-dihydro(leuco)-1,4-dihydroxyanthracene-9,10-dione. To this reaction mixture is added dropwise 20 g (0.17 mol) of 2-(diethylamino)-ethylamine over a 30 minute period. The mixture is heated at 50°-55° C. for 2 hours and 20 ml of ethanol are added. The solution is then aerated and 200 ml of 2M hydrochloric acid are added. The acidic mixture is washed with 3×200 ml of diethylether followed by 3×200 ml of chloroform. The aqueous phase is made alkaline by the addition of sodium hydroxide solution and extracted with 3×200 ml chloroform. The mixture is evaporated in vacuo to a 5 ml volume and subjected to flash chromatography using a column of 70-230 mesh (60 A) silica gel (SiO2) and an eluting solvent of chloroform followed by chloroform:methanol (1:1 v/v). The blue black material removed from the column in chloroform/methanol is evaporated in vacuo to yield 0.7 g of the title compound, m.p. 107.5°-108.5° C.; λmax λmax (deionised water) (E/cm/M) 256 nm (50950), 584 nm (18650).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.[Br:17]Br>C(O)(=O)C.C1(C)C=CC=CC=1>[Br:17][CH2:15][C:14]([C:4]1[CH:5]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:16]
Reactant: CC(=O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: BrBr
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(CBr)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[3-Bromo-5-(pentafluorosulfanyl)phenyl]ethanone (50 mg) was initially charged dissolved in glacial acetic acid (3 ml), and bromine (50 μl of a solution of 475 mg of bromine in 1 ml of glacial acetic acid) was slowly added dropwise. After stirring at RT for 30 min, the mixture was heated to 60° C. for 3 h and then a further 15 μl of the bromine solution were added. After 2 h, the mixture was left to stand overnight, then heated again to 60° C., and a further 10 μl of the bromine solution were added. After 1 h, the mixture was diluted with toluene and dried. The residue was purified by means of preparative HPLC, and the product-containing fractions were combined, freed of the acetonitrile, alkalized with saturated sodium hydrogencarbonate solution and extracted three times with EA. The combined EA phases were dried over magnesium sulfate, filtered and concentrated. 16 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C([Li])CCC.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.Cl>CCOCC>[Br:8][C:4]1[N:3]=[C:2]([CH:19]([OH:20])[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Brc1cccc(Br)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC(c1ccc(Cl)cc1)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a stirred solution of 2,6-dibromopyridine (100 g) in dry ether (1 l) under nitrogen at -70° was added dropwise during 2 hr a solution of n-butyllithium (270 mL, 1.7M in hexane). After an additional 0.5 hr, a solution of p-chlorobenzaldehyde (65 g) in dry ether (500 mL) was added during a 1 hr period. The reaction mixture was allowed to warm to ca. 0° and then poured into aqueous hydrochloric acid (1 l, 4N). The ether layer was separated and the aqueous layer was extracted with two additional portions (300 mL) of ether. The combined ether layers were washed with water (500 mL), dried (Na2SO4) and concentrated to give a syrup. The crude product was chromatographed on silica gel using the Waters Prep 500 (trademark of Waters Associates Inc., Milford, MA 01757) with methylene chloride to provide α-(6-bromo-2-pyridyl)-4-chlorobenzyl alcohol (93.8 g), m.p. 64.5°-65°.
Reaction SMILES: [NH4+:1].[OH-].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15](Cl)=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([NH2:1])=[O:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2)o1
Agent: [OH-]
Product: NC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Reaction time: 0.25 h

Procedure:
To 1000 ml. of cold, stirring NH4OH, 63 g. (0.26 mole) of 5-(p-chlorophenyl)-2-furoyl chloride is added portionwise. The resulting mixture is stirred at ice bath temperature for 15 minutes and then is stored at room temperature for 18 hours. The solid is filtered, is washed with water and is dried at 60 to yield 56 g. (97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:17][C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccncc1
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C=Cc2ccncc2)cc1

Procedure:
By the procedure described in Ex. 1, 4-methoxybenzaldehyde (17 g) and 4-picoline (9.3 g) 4.76 g were reacted to obtain 4-(4-methoxystyryl)pyridine.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH:18](OC)=[O:19]>C1COCC1>[CH:18]([CH:13]([CH2:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:19]
Reactant: COC=O
Reactant: COC(=O)CCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 1.38 g of 60% NaH was suspended in 12 ml of THF. Then, 2.4 g of methyl 3-(3,4-methylenedioxyphenyl)-propionate was dissolved in 12 ml of THF and added dropwise to the suspension solution prepared above at room temperature. After the suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 3.46 g of methyl formate was added dropwise for 1 hour. Further, 0.7 g of 60% NaH and 0.9 g of methyl formate were divided into four parts and each part was added separately. Afterwards, the solution mixture was stirred at 40° C. for 3 hours.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[C:6]([NH:13][S:14]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])(=[O:16])=[O:15])[CH:5]=1.Br[CH2:28][CH2:29]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]2[O:12][CH2:29][CH2:28][N:13]([S:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[O:24][CH3:25])(=[O:16])=[O:15])[C:6]=2[CH:5]=1)=[O:26]
Reactant: BrCCBr
Reactant: COC(=O)c1cc(NS(=O)(=O)c2cc(Cl)ccc2OC)c(O)c(OC)c1
Product: COC(=O)c1cc(OC)c2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=531.1 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-5-methoxy-benzoic acid methyl ester (example 42, step 2) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzene-sulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 4-aminobenzoate in step 3 to produce 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-8-methoxy-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: [CH3:1][S:2]([CH2:4][C:5]([C:7]1[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])=O.C1C=CC=CC=1.FC(F)(F)C(O)=O>>[C:10]([N:9]1[C:8]2[C:7](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:6])[CH:4]1[S:2][CH3:1])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)CC(=O)c1ccccc1NC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC1C(=O)c2ccccc2N1C(=O)c1ccccc1
Yield: 68.4 %

Procedure:
2'-[(methylsulfinyl)-acetyl]benzanilide (7 g) is refluxed in benzene containing 1 equivalent of trifluoroacetic acid for 1 hour. The solvents are removed under reduced pressure to give an oil which crystallizes on standing. Recrystallization from ethyl acetate gives 1-benzoyl-2-(methylthio)-3-indolinone (4.5 g 67%) m.p. 126°-128° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2].[I-].[Na+].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C>[C:1]([NH:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:7]([O:19][CH3:20])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCCl
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)CCCCN1CCCCC1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentan-1-one (0.72 g, 2.26 mmol), sodium iodide (0.15 g, 0.1 mmol), and piperidine (1.72 g, 20 mmol) were combined in DMF (8.0 mL) and the mixture was heated to 80° C. for 4.5 hours. Water was then added to form a precipitate. Filtration gave 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-(piperidin-1-yl)pentan-1-one (0.8 g, 2.18 mmol), m.p. 74°-75° C.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6]OC2(C)C)[CH:3]1[CH:12]([CH3:14])C.[Si:15](N1C(C=C)CC1=O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O=C1N2C(CCOC2(C)C)C1.C(I)C>>[CH2:12]([CH:3]1[CH:4]([CH:5]=[CH2:6])[N:9]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:2]1=[O:1])[CH3:14]
Reactant: C=CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Agent: CC1(C)OCCC2CC(=O)N21
Solvent: CCI
Product: C=CC1C(CC)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Following the procedure for the preparation of 8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 4b, above), except that an equivalent amount of 1-(t-butyl-dimethylsilyl)-4-vinyl-2-azetidinone is substituted for the 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane of Example 4b and using ethyl iodide instead of isopropyl iodide, the title compound is obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:19]([O:21][CH3:22])=[O:20])[C:3]1=[O:23].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:19]([O:21][CH3:22])=[O:20])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[C:3]2=[O:23])[CH2:12][CH2:11]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)C1=O
Yield: 38 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butyl(methyl)amino)-cyclohexanecarboxylate (58 mg, 0.18 mmol), 3-(trifluoromethyl)benzoic acid (42 mg, 0.22 mol), EDCI (30 mg, 0.21 mmol), HOBT (30 mg, 0.21 mmol), and Et3N (21 mg 0.21 mmol) in CH2Cl2 was stirred overnight at room temperature. The solution was washed with water and brine, concentrated in vacuo and the residue chromatographed on silica gel (3%–5%–10% (NH4OH/MeOH)/CH2Cl2) to give 34 mg of the title product, (1R,2S,5R)-methyl 5-(tert-butyl(methyl)amino)-2-((S)-2-oxo-3-(3-(trifluoromethyl)-benzamido)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=498.40.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:17])[CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Br)cc1C=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A solution of 5-bromo-2-methoxybenzaldehyde (100 g, 0.46 mol) in CHCl3 (150 ml) was cooled with an ice bath and 3-chloroperoxybenzoic acid (50-60% purity) (146 g, 0.51 mol) in CHCl3 (1000 ml) added. The reaction mixture was allowed to warm slowly to room temperature and stirred for 72 h. The white solid was filtered off and the filtrate concentrated in vacuo. The residue was dissolved in Et2O (200 ml) and washed with 1M sodium sulphite solution (2×200 ml) then NaHCO3 [half saturated] (3×200 ml). The ether layer was washed with 10% aqueous NaOH (3×100 ml) and the combined basic extract was acidified with concentrated hydrochloric acid and extracted with Et2O (3×100 ml). The combined organic extract was dried (MgSO4) and florisil (10 g) filtered and the solvent removed under reduced pressure to give the title compound (90 g) as a pale brown solid.