Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][C:17]1=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28]>O1CCCC1>[F:23][C:24]1[CH:25]=[C:26]([C@H:27]([OH:28])[C@H:18]2[O:19][CH2:20][CH2:21][N:16]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:17]2=[O:22])[CH:29]=[CH:30][CH:31]=1.[F:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:28])[C@@H:18]2[O:19][CH2:20][CH2:21][N:16]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:17]2=[O:22])[CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1cccc(F)c1
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1[C@@H]([C@@H](O)c2cccc(F)c2)OCCN1Cc1ccccc1
Product: O=C1[C@H]([C@H](O)c2cccc(F)c2)OCCN1Cc1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of lithium diisopropylamide (2M in heptane, 16.9 ml) was added dropwise over 15 min to a stirred solution of 4-benzyl-morpholin-3-one (5.0 g, 26 mmol) and 3-fluorobenzaldehyde (3.55 g, 28.6 mmol) in dried tetrahydrofuran (60 ml) cooled to −70° C. under nitrogen atmosphere. After 1 h at −70° C., the reaction mixture was quenched with aqueous ammonium chloride (100 ml) and extracted with ethyl acetate (100 ml). The extracts were washed with 2M aqueous hydrochloric acid (2×50 ml), brine solution (100 ml) and dried over sodium sulphate. After filtration, the solution was evaporated and the residual oil purified by chromatography on silica eluting with ethyl acetate:hexane 70:30 then ethyl acetate to give diastereomer 1 (2R)-2-[(S)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one and (2S)-2-[(R)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one as a solid (3.8 g) followed by diastereomer 2 (2R)-2-[(R)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one and (2S)-2-[(S)-(3-fluorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one as an oil (2.13 g). Diastereomer 1 was recrystallised from ethyl acetate (25 ml) n-hexane (100 ml) to give white needles (2.62 g, 32%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:22]=[CH:21][C:20]2[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([C:23](=[O:35])[CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([OH:34])=[O:33])=[CH:28][CH:27]=3)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].CO>O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:23]([C@H:14]2[CH2:13][CH2:12][C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]23[CH3:16])[C:20]2[CH:21]=[CH:22][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[CH2:8][CH2:9]4)=[O:35])=[CH:31][CH:30]=1)([OH:34])=[O:33]
Reactant: COC(=O)c1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CCc3ccc(C(=O)O)cc3)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12CC[C@@H]3c4ccc(C(=O)O)cc4CC[C@H]3[C@@H]1CC[C@@H]2C(=O)CCc1ccc(C(=O)O)cc1
Yield: 79 %

Procedure:
A mixture of methyl-17β-[3-(4-carboxyphenyl)propionyl]-estra-1,3,5(10)-triene-3-carboxylate (0.053 g, 0.11 mmoles), K2CO3 (50 mg, 0.36 mmoles), MeOH (9 ml) and H2O (1 ml) was refluxed under argon. Methanol was evaporated and the residue was acidified with dilute HCl. Extracted with EtOAc. The organic layer was washed with H2O, brine, dried and concentrated. The residue was chromatographed (silica gel) eluting with 1% MeOH in CH2Cl2 containing 1% HOAC to give the title compound as a white solid (40 mg, 80%), mp 285°-290° C.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]([CH3:21])[C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:9]=[C:8]([C:19]#[N:20])[CH:7]=1.[Cl-:22].[NH4+:23].C(O)(=O)C>CO>[ClH:22].[CH3:4][N:5]([CH3:21])[C:6]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:9]=[C:8]([C:19](=[NH:23])[NH2:20])[CH:7]=1
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CN(C)c1cc(C#N)nn1Cc1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)c1cc(C(=N)N)nn1Cc1ccccc1F
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
356 mg of sodium methanolate (6.60 mmol, 4.0 eq.) were dissolved in 10 mL of methanol. 403 mg of 5-(dimethylamino)-1-(2-fluorobenzyl)-1H-pyrazole-3-carbonitrile 1-11-1 (1.65 mmol, 1.0 eq.) were dissolved in 20 mL of methanol and added dropwise. The mixture was stirred for one hour at rt. 111.2 mg of ammonium chloride (2.08 mmol, 1.26 eq.) and 377 μL of 100% acetic acid (6.60 mmol, 4.0 eq.) were added and stirred under reflux for 24 hours. 111 mg of ammonium chloride (2.08 mmol, 1.26 eq.) and 377 μL of 100% acetic acid (6.60 mmol, 4.0 eq.) were added and stirred under reflux for 24 hours again. The mixture was concentrated under vacuo. The residue was suspended in acetonitrile and filtered off two times. The filter cakes were dissolved in DCM/methanol 1:1 and filtered over a silica column to provide 313 mg (1.19 mmol, 72.6%) of analytically pure target compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:4][C:3]=1[O:18][CH3:19].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>>[Si:24]([O:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]([CH:10]=[CH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])=[CH:6][C:7]=1[O:8][CH3:9])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25]
Reactant: COc1cc(C=CC(=O)CC(C)=O)cc(OC)c1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: COc1cc(C=CC(=O)CC(C)=O)cc(OC)c1O[Si](C)(C)C(C)(C)C

Procedure:
According to the procedure of Example 22C, 1-(4'-hydroxy-3',5'-dimethoxyphenyl)-1-hexene-3,5-dione is reacted with t-butylchlorodimethyl silane to afford 1-(4'-t-butyldimethylsilyloxy-3',5'-dimethoxyphenyl)-1-hexene-3,5-dione suitably pure for further use.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1>C(O)(=O)C>[O:11]=[C:1]1[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:6])[N:12]1[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1

Procedure:
Phthalic acid anhydride (15.1 g, 102 mmol) and 4-amino phenyl acetic acid (15.2 g, 102 mmol) were dissolved in acetic acid and heated at reflux for 1 hour. Upon cooling on an ice bath, the product crystallized. The solid was filtered off, washed with water, and dried under vacuum overnight. The yield of the title compound was 24.1 g (86%) as an off white solid.
Reaction SMILES: N1C=CC=CC=1.C(Cl)Cl.[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][OH:16]>CC(C)=O>[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([S:27](=[O:30])(=[O:29])[NH2:28])[C:19]=1[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]=[O:16]
Reactant: CNc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of dry pyridine (15 ml) and dry methylene chloride (225 ml), chromic anhydride (9.0 g) is added in one portion, and the mixture is stirred for 15 minutes. A solution of 3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol (4.6 g; prepared as described in Example 5) in acetone (25 ml) is then added in one portion and the mixture is stirred for a further 15 minutes. The resulting inorganic precipitate is removed by filtration and the filtrate is evaporated in vacuo. The residue is extracted with diethyl ether (300 ml) and filtered to remove a small amount of insoluble material. The diethyl ether is removed in vacuo to yield crude 3-methylamino-4-phenoxy-5-sulfamylbenzaldehyde. After recrystallization from ethanol it is obtained with a melting point of 166°-167° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C@@:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])([CH3:15])[C@@H:13]2[C@@H:9]([CH2:10][O:11][CH2:12]2)[O:8][S:7]1=[O:23].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>C(OCC)(=O)C.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C@@:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])([CH3:15])[C@@H:13]2[C@@H:9]([CH2:10][O:11][CH2:12]2)[O:8][S:7]1(=[O:31])=[O:23]
Reactant: COc1ccc(CN2S(=O)O[C@@H]3COC[C@@H]3[C@@]2(C)c2ccccc2F)c(OC)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(CN2[C@](C)(c3ccccc3F)[C@H]3COC[C@H]3OS2(=O)=O)c(OC)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A solution of (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5-oxide (7.24 g, 17.2 mmol) and sodium periodate (4.04 g, 18.9 mmol) in a mixture of ethyl acetate (60 ml), acetonitrile (60 ml) and cold water (99.6 ml) was treated with ruthenium(III) chloride (35.6 mg, 172 μmol). The reaction mixture was stirred at 23° C. for 30 minutes. For the workup, the reaction mixture was extracted with a saturated solution of sodium hydrogencarbonate, the aqueous layer re-extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide (4.1 g, 55% yield) was obtained as a light yellow solid. MS (ISP): m/z=460.2 [M+Na]+.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]2[CH2:18][CH2:19][C:20]([NH:22][CH3:23])=[O:21])=O)=CC=1)([O-])=O.[H][H]>O1CCCC1.C(O)C.[C].[Pd]>[CH3:23][NH:22][C:20]([CH2:19][CH2:18][C@@H:13]1[CH2:14][C@@H:15]([OH:17])[CH2:16][NH:12]1)=[O:21]
Reactant: CNC(=O)CC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)CC[C@@H]1C[C@@H](O)CN1

Procedure:
To a solution of (2R,4R)-1-p-nitrobenzyloxycarbonyl-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine (1.52 g) in tetrahydrofuran (15 ml) and ethanol (15 ml), 10 palladium-carbon (228 mg) was added. The mixture was stirred at room temperature for 3.5 hours under an atmospheric pressure of hydrogen. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated, and the residue was combined with water, washed with dichloromethane and lyophilized to give (2R,4R)-2-(2-methylaminocarbonylethyl)-4-hydroxypyrrolidine.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[C:26]([Cl:30])=[C:27]([Cl:29])[S:28][C:23]=2[CH:22]=1)=[O:20])=[O:7])(=O)C.CO.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:29][C:27]1[S:28][C:23]2[CH:22]=[C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[O:20])[NH:25][C:24]=2[C:26]=1[Cl:30]
Reactant: CC(=O)OCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CO)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
N-{(1R,2R)-1-[(2-Acetoxyacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Example 6; 632 mg, 1.36 mmol) was dissolved in THF (10 mL), MeOH (10 mL) and K2CO3 (100 mg) were then added and the suspension stirred at ambient temperature for 16 hours. Water (50 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc:isohexane, 1:10), filtered, washed with isohexane (5 mL) and dried to give the title compound (428 mg, 74%) as a white solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:10]([CH2:13][CH3:14])CC)C.[C:15]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1.Cl>C(Cl)Cl.O>[CH:1]1([NH:7][C:28](=[O:29])[CH2:27][CH2:26][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([NH:10][CH:13]3[CH2:14][CH2:3][CH2:2][CH2:1][CH2:6]3)=[O:24])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCc1ccc(CCC(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccc(CCC(=O)NC2CCCCC2)cc1)NC1CCCCC1
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 4.9 g of cyclohexylamine and 5.4 g of triethylamine in 100 ml of methylenechloride, was added 5.8 g of 1,4-phenylenedipropionyl chloride under ice cooling with stirring. Stirring was continued for 3 hours at room temperature, and 500 ml of water was added to the reaction solution. Conc.-HCl was added to the mixture until aqueous layer became weak-acidic. The solid material precipitated was collected by filtration, washed with methylenechloride and water in that order, and dried, giving 7.4 g of N,N'-dicyclohexyl-1,4-phenylenedipropionamide.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.C1(P(=[CH:30]/[CH:31]=[CH:32]/[CH:33]=[O:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[O:34]=[CH:33]/[CH:32]=[CH:31]/[CH:30]=[CH:1]/[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: O=C/C=C/C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: N#Cc1ccc(/C=C/C=C/C=O)cc1

Procedure:
A solution of 3.1 g (99 mmol) of 4-formylbenzonitrile (commercially available) and 40 g (120 mmol) of (triphenylphosphoranylidene)crotonaldehyde [prepared as described in Tetrahedron Lett., 493 (1971)] in 200 ml of dichloromethane was stirred at ambient temperature overnight. At the end of this time, the reaction mixture was concentrated to dryness in vacuo. The resulting residue was purified by chromatography on a silica gel (250 g) column using ethyl acetate as the eluant to give a mixture of the desired compound and a Geometrical isomer thereof. A solution of the mixture of the two isomers in 150 ml of toluene was heated at reflux under irradiation with a tungsten lamp (300 W) for 12 hours. The reaction mixture was then concentrated in vacuo. The resulting residue was purified by chromatography on a silica gel (1.2 kg) column using a 1:9 mixture of ethyl acetate and toluene as the eluant to afford 3.46 g (yield 19%) of the title compound as pale brown needle-like crystals which were collected by filtration.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25]C(=O)C)=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[OH-].[Na+].O.CCOC(C)=O>CC(O)=O>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:15][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[NH:5][C:4]2[CH2:3][N:2]([CH3:1])[CH2:14][CH2:13][C:12]3=2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc3[nH]c4c(c3c2)CCN(C)C4)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN1CCc2c([nH]c3ccc(NS(=O)(=O)c4ccc(N)cc4)cc23)C1
Yield: 70.1 %

Procedure:
A solution of N-[4-(2-Methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-ylsulfamoyl)-phenyl]-acetamide (example 7) (80 mg, 0.2 mmol) in 1 mL of an aqueous 10% de NaOH solution was refluxed for 2 h. The resulting mixture was treated with H2O (25 mL) and EtOAc (25 mL) and neutralized by addition of AcOH glacial. The aqueous phase was washed again with EtOAc and the combined organic extracts dried to afford 50 mg of 4-amino-N-(2-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-yl)-benzenesulfonamide as a cream colored amorphous solid, mp 236-237° C. 1H-NMR (300 MHz, DMSO-d6): (ppm) 2.36 (s, 3H); 2.55 (bb, 2H); 2.61 (bb, 2H); 3.45 (bb, 2H); 5.83 (bb, 2H); 6.44 (sys AB, 2H, J=8.7 Hz); 6.68 (dd, 1H, J=8.4, 1.8 Hz); 6.99 (bb, 1H); 7.05 (d, 1H, J=8.4 Hz); 7.25 (sys AB, 2H, J=8.7 Hz); 9.27 (s, 1H); 10.63 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C@@:9]1([CH3:18])[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][CH2:10][C@@:9]1([CH3:18])[C:15]([O:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@]1(C(=O)O)COCC(=O)N1Cc1ccccc1
Reactant: BrCc1ccccc1
Product: C[C@@]1(C(=O)OCc2ccccc2)COCC(=O)N1Cc1ccccc1
Yield: 70.1 %

Procedure:
(S)-4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (2.49 g, 10 mmol) was reacted with benzyl bromide (2.05 g, 12 mmol) according to the procedure as described in Example 34, Step A to give the title compound as colorless oil (2.38 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([O:30][CH3:31])[C:27](O)=[O:28]>>[F:19][C:20]1[CH:21]=[C:22]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:23][NH:24][C:25](=[O:32])[CH:26]([O:30][CH3:31])[C:27]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:28]
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Reactant: COC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: COC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=480.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and N-(3,5-difluoro-benzyl)-2-methoxy-malonamic acid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Cl-:1].[C:3]1([CH2:2][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: ClCc1cccc2ccccc12
Solvent: CN(C)C=O
Product: [Cl-]
Product: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reaction time: 5 h
Yield: 90.9 %

Procedure:
A mixture of 5.3 g (0.03 mole) of 1-(chloromethyl)naphthalene and 8.6556 g (0.033 mole) of triphenylphosphine in 150 mL of dimethylformamide was heated at reflux with stirring for 5 hours. A copious white precipitate formed. The precipitate was filtered and washed with 100 mL of dimethylformamide and 100 mL of ether. The product was dried in vacuo to yield 11.97 g (91%) of 1-naphthylmethyltriphenylphosphonium chloride as white crystals: mp 285°-288°; IR (KBr) 3050, 3010, 2880, 2790, 1665, 1590, 1510, 1485, 1440, 1385, 1335, 1275, 1155, 1110, 1095, 875, 810, 785, 730, and 690 cm-1 ; NMR (DMSO) δ5.67 (d, J=15 Hz, 2H), 7.60 (m, 15H) and 7.73 (m, 7H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1C=CC=CC=1.[CH3:25][CH:26]([N:28]1[C:32]([NH2:33])=[CH:31][CH:30]=[N:29]1)[CH3:27]>C(O)(=O)C>[CH3:25][CH:26]([N:28]1[C:32]2[N:33]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:31]=2[CH:30]=[N:29]1)[CH3:27]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(SC)cc1
Reactant: CC(C)n1nccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(SC)cc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 4-[4-(methylthio)phenyl]-2,4-dioxobutanoate (851 mg, 3.20 mmol), benzene (6 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 3.20 mmol), and acetic acid (3 mL). The crude product was purified by column chromatography (Silica gel, eluent; 0 to 100% EtOAc/hexanes) to give 870 mg (63%) of product. LCMS E-S (M+H)=433.2. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47-1.57 (m, 3H), 1.66 (d, J=6.8 Hz, 6H), 2.58 (s, 3H), 4.56 (q, J=7.2 Hz, 2H), 5.38-5.55 (m, 1H), 7.36-7.46 (m, 2H), 8.12-8.19 (m, 2H), 8.22 (s, 1H), 8.40 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15].[Cl-].[Na+].O.CCOC(C)=O>CS(C)=O>[CH3:17][O:16][C:14](=[O:15])[CH2:13][C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A mixture of dimethyl 2-(2-chloro-5-methoxy-4-nitrophenyl)malonate (3.0 g, 9.44 mmol) and sodium chloride (0.99 g, 16.99 mmol) in DMSO (50 mL) and water (0.17 mL, 9.44 mmol) was heated for 5 hours at 120° C. The reaction mass was allowed to cool to room temperature and water (400 mL) and EtOAc (50 mL) were added and stirring continued for 15 minutes. The separated aqueous layer was extracted with EtOAc (50 mL), and then the combined organic layers were washed with brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography on neutral silica gel using 15-25% EtOAc in hexane to give the desired material (1.5 g, 61%) as a solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].N[C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([Cl:20])[N:14]=1.CCN(CC)CC>C(O)(C)C>[Cl:20][C:15]1[N:14]=[CH:13][N:18]=[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])[CH:16]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 90 °C
Yield: 143.3 %

Procedure:
To a solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol HCl (1.00 g, 5.44 mmol) and 2-amino-4,6-dichloropyrimidine (0.982 g, 5.99 mmol) in isopropyl alcohol (8 mL) was added Et3N (1.90 mL, 13.6 mmol). The reaction was heated to 90° C. for 1 h in an oil bath then cooled, filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash chromatography (20 to 50% MeOH/CH2Cl2) to afford the title compound as an off-white solid (2.025 g, >99%). LC/MS: Rt=0.81 min ES 260 (FA standard).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=2[Br:35])=[CH:20][C:16]=1[C:17]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:18]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reactant: OC1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCOC1)c1cc(Oc2ccc(C(F)(F)F)cc2Br)ccc1Cl
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-chloro-5-(2-bromo-4-trifluoromethylphenoxy)benzoate.