Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.O[CH:7]([C:9]1[CH:10]=[C:11]([S:25]([NH2:28])(=[O:27])=[O:26])[S:12][C:13]=1[S:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:8].C([O-])(O)=[O:30].[Na+].[C:34](#[N:36])[CH3:35]>O>[C:34]([NH:36][CH:7]([C:9]1[CH:10]=[C:11]([S:25]([NH2:28])(=[O:26])=[O:27])[S:12][C:13]=1[S:14]([C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[CH3:8])(=[O:30])[CH3:35]
Reactant: COc1ccc(S(=O)(=O)c2sc(S(N)(=O)=O)cc2C(C)O)cc1
Reactant: CC#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1ccc(S(=O)(=O)c2sc(S(N)(=O)=O)cc2C(C)NC(C)=O)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Acetonitrile (30 ml) was cooled in ice and concentrated H2SO4 (4.4 ml, 0.083 mol) was added over about 5 minutes. Then 4-(1-hydroxyethyl)-5-(4-methoxyphenylsulfonyl)thiophene-2-sulfonamide (3.13 g, 0.0083 mol) in acetonitrile (20 ml) was added and the solution was stirred at room temperature over the week-end. The reaction was diluted with water (10 ml) and was neutralized with NaHCO3. The suspension was filtered and the solids were washed with acetonitrile. The filtrate and washings were concentrated in vacuo. The residual oil was taken up in ethyl acetate and water. The ethyl acetate was separated, washed with saturated NaCl, dried, filtered and concentrated in vacuo. A white solid foam was obtained, 3.18 g, yield 92%. The structure was supported by NMR analyses.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([OH:29])[CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.O[C:31]1[CH:39]=[CH:38][C:37]([C:40](=O)[CH2:41]Br)=[CH:36][C:32]=1C(O)=O.O=C1N(C2CCNCC2)[C:48]2[CH:56]=[CH:57]C=C[C:47]=2[NH:46]1.OC1C=CC(C(=O)CN2CCC(N3C4C=CC=CC=4NC3=O)CC2)=CC=1C(O)=O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([OH:29])[CH2:12][N:13]2[CH2:14][CH:15]=[C:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:17][CH2:18]2)=[CH:7][C:3]=1[C:4]([NH:46][CH2:47][CH2:48][CH2:56][CH2:57][CH2:41][CH2:40][CH2:37][CH2:38][CH2:39][CH2:31][CH2:32][CH3:36])=[O:6]
Reactant: O=C(O)c1cc(C(O)CN2CCC(n3c(=O)[nH]c4ccccc43)CC2)ccc1O
Reactant: O=C(CBr)c1ccc(O)c(C(=O)O)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(O)c(C(=O)O)c1
Product: CCCCCCCCCCCCNC(=O)c1cc(C(O)CN2CC=C(n3c(=O)[nH]c4ccccc43)CC2)ccc1O

Procedure:
The 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)piperidino]ethyl]benzoic acid derivatives of formula (I) are readily prepared by condensing a derivative of 2-hydroxy-5-(2-bromoacetyl)benzoic acid (II) with a 4-(2-oxo-1-benzimidazolinyl)piperidine (III). The resulting 2-hydroxy-5-[4-(2-oxo-1-benzimidazolinyl)piperidinoacetyl]benzoic acid derivative (IV) is subsequently reduced to the desired derivative of 2-hydroxy-5-[1-hydroxy-2-[4-(2-oxo-1-benzimidazolinyl)piperidino]ethyl]benzoic acid (I). This process may be schematically illustrated as follows: ##STR2##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH:18]=O)[CH2:13]1>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:14]1[CH2:15][CH2:16][CH2:17][O:12][CH2:13]1)[CH2:9][C:8]2=[O:10]
Reactant: O=CC1CCCOC1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: O
Solvent: CCO
Product: O=C1CC(C2CCCOC2)Oc2ccc(Br)cc21
Yield: 17.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxyphenyl)ethanone (39 g, 181.8 mmol), tetrahydro-2H-pyran-3-carbaldehyde (20 g, 181.8 mmol) and borax (69.3 g, 181.8 mmol) in ethanol (240 mL) and H2O (400 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-2-(tetrahydro-2H-pyran-3-yl)chroman-4-one (10 g, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.Cl[C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[IH:19]>>[I:19][C:12]1[CH:17]=[C:16]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=2)[N:15]=[CH:14][N:13]=1
Reactant: I
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: Clc1cc(Cl)ncn1
Product: Clc1ccc(-c2cc(I)ncn2)cn1

Procedure:
The compound was prepared according to Example 1 using 2-chloropyridine-5-boronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:9]([OH:24])[CH:8]=1)[CH3:2].[C:26]([O-])([O-])=O.[K+].[K+].CI.[F-].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][NH:15][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[C:9]([O:24][CH3:26])[CH:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)c(O)c1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)c(OC)c1
Reaction time: 3 h

Procedure:
To a vigorously stirred solution of the compound of example 41e (4.5 g; 12.7 mmol) in dry DMF (20 ml) was added sequentially fused K2CO3 (3.5 g; 25.5 mmol), methyl iodide (0.96 ml; 15.3 mmol) and KF (0.45 g). The reaction mixture was stirred for 3 h, diluted with water (200 ml) and the oily residue was extracted with chloroform (3×30 ml). The organic layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform). Yield, 3.25 g (69.5%); mp, 75° C.; MS (ESI+): 390 (M++Na), 368 (M++1); analysis: C18H25NO7 requires C, 58.85; H, 6.85; N, 3.81; found: C, 58.79; H, 7.26; N, 3.81%.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:26]([CH3:27])[C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:24][N:23]=1>>[ClH:17].[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:26]([CH3:27])[C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)=[N:24][N:23]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: Cn1c(SCCCCl)nnc1-c1ccc(C(F)(F)F)cc1
Reactant: CCc1nc2cc3c(cc2o1)CCNCC3
Product: CCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2ccc(C(F)(F)F)cc2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.25 mmol) and 3-[(3-chloropropyl)thio]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazole and was obtained as a faint yellow slightly hygroscopic solid (0.074 mmol).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:6]2[CH:7]=[C:2]([Br:1])[N:3]=[CH:4][C:5]2=[O:8])=[CH:12][CH:13]=1
Reactant: O=c1cnc(Br)c[nH]1
Reactant: Clc1ccc(CBr)cc1
Solvent: CC#N
Product: O=c1cnc(Br)cn1Cc1ccc(Cl)cc1
Yield: 86.7 %

Procedure:
According to Scheme 27 Step 1: The title compound was prepared from 5-bromopyrazin-2(1H)-one (1 eq, 2.86 mmol, 0.50 g) and 1-(bromomethyl)-4-chlorobenzene (1.5 eq, 4.29 mmol, 0.88 g) according to the procedure described for Example 1 Step 2. Reaction conditions: 3 hours at 70° C. in acetonitrile. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using pure AcOEt as eluent to afford 1-(4-chlorobenzyl)-5-bromopyrazin-2(1H)-one (2.48 mmol, 0.74 g, 87%) as a white solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([N:14]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:29](=[O:30])[CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)NCC1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of C-(1-Benzhydryl-pyrrolidin-3-yl)-methylamine (0.26 g, 0.98 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropionic acid (0.22 g, 0.98 mmol) under nitrogen. To the reaction was added EDC (0.37 g, 1.95 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (20 ml, 2×) and 10% NaOH (20 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (15:1) to give a desired product in good yield
Reaction SMILES: [Si](Cl)(C(C)(C)C)(C)C.[C:9](OCC)(=O)[C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11].[NH:22]1C=CN=C1>CN(C)C=O>[NH2:22][CH2:9][C@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[OH:11]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)[C@@H](O)c1ccccc1
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: NC[C@@H](O)c1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A solution of 31.4 g of t-butyldimethylsilyl chloride in 200 ml of dimethylformamide was added dropwise to a solution of 25 g of ethyl (S)-(+)-mandelate and 28.4 g of imidazole in 800 ml of dimethylformamide, and the resulting mixture was stirred overnight at 40° C. At the end of this time, the dimethylformamide solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give the title compound having an Rf=0.84 (thin layer chromatography over silica gel, using a 10: 1by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].Cl[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COC(=O)C(C)Cl
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccc(C(C)=O)cc1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of the potassium salt of 4-hydroxyacetophenone (25.0 g, 0.14 mol) in dimethylformamide (DMF) (100 mL) is added methyl 2-chloropropanoate (24.5 g, 0.20 mol) over 30 minutes and stirred as 85°-90° C. for 3 hours under nitrogen. The reaction is filtered to remove KCl and the filtrate is concentrated under reduced pressure to remove DMF and the product analyzed by GLC. The product is dissolved in ethyl acetate (300 mL) and extracted with 2N NaOH (2×100 mL) and water (100 mL). The organic phase is dried and concentrated to give pure methyl 2-(4-acetylphenoxy)propanoate (25 g) (yield 64%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.[Br:11]Br>C(Cl)Cl>[Br:11][CH:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: BrBr
Solvent: ClCCl
Product: CC1(C)OC(C)(C)C(Br)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of commercially available 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich, 10.0 g, 0.07 mol) in CH2Cl2 (100 mL) was added bromine (Aldrich, 3.6 mL, 0.07 mol,) dropwise at room temperature. The reaction mixture was stirred for 2 hours over which time the reaction mixture became clear. Then, the reaction mixture was cooled to 0° C., quenched with NaHCO3 powder in small portions, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 1.26 (s, 3H), 1.27 (s, 3H), 1.30 (s, 3H), 1.39 (s, 3H), 5.22 (s, 1H).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[S:5][CH2:6][CH2:7][N:8]=1.[H][H].[O:11]([C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[O:11]([C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][S:3][C:4]2[S:5][CH2:6][CH2:7][N:8]=2)=[CH:26][CH:27]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: SC1=NCCS1
Reactant: [H][H]
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Oc2ccc(OCCSC3=NCCS3)cc2)cc1
Yield: 66.9 %

Procedure:
To a suspension of sodium hydride (160 mg, 4.0 mmol; 60% in oil) in dimethylformamide (5 ml), a solution of 2-mercapto-2-thiazoline (476 mg, 4.0 mmol) in dimethylformamide (3 ml) was dropwise added with stirring, and stirring was continued until the generation of hydrogen gas ceased. To the resultant solution, there was dropwise added a solution of 2-(4-phenoxyphenoxy)ethyl bromide (1.17 g, 4.0 mmol) in dimethylformamide (3 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water (80 ml) and extracted with toluene (40 ml) three times. The toluene layer was dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residue was purified by silica gel column chromatography to give 2-[2-(4-phenoxyphenoxy)ethylthio]-2-thiazoline (887 mg) as pale yellow crystals. M.P., 88.6° C.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH:12]1([CH:15]=[O:16])[CH2:14][CH2:13]1.[N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]>ClCCl>[OH:18][N:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([CH:12]1[CH2:14][CH2:13]1)=[O:16]
Reactant: O=CC1CC1
Reactant: O=Nc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(C1CC1)N(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DBU (15 mg, 0.1 mmol) was added under argon to a solution of cyclopropanal (70 mg, 1 mmol), nitrosobenzene (107 mg, 1 mmol) and catalyst (36.4 mg, 0.1 mmol) in dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 10 min. The solvent was removed under vacuum, and the residue was purified by flash silica gel column chromatography using hexane and ethyl acetate as the eluents.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]2[CH2:16][CH2:15]2)[CH2:12][N:11]2[N:17]=[C:18]([I:23])[C:19]([C:20]([OH:22])=O)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:27](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:20]([C:19]1[C:18]([I:23])=[N:17][N:11]2[CH2:12][CH:13]([CH:14]3[CH2:15][CH2:16]3)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C:10]=12)(=[O:22])[NH2:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC1C1CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2CC1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a stirred solution of Intermediate 348F (0.75 g, 1.731 mmol) in DMF (4.0 mL) was added NH4Cl (0.463 g, 8.66 mmol), HATU (1.316 g, 3.46 mmol) and DIPEA (1.512 mL, 8.66 mmol) and the resulting solution was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (24 g REDISEP® column, eluting with 65% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 348G as a colorless liquid (0.51 g, 68%). MS(ES): m/z=433 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 6.83-7.50 (m, 2H), 5.07 (d, J=18.13 Hz, 1H), 4.50 (d, J=18.51 Hz, 1H), 4.20 (d, J=2.27 Hz, 2H), 3.84 (br. s., 1H), 1.43 (s, 9H), 0.89 (d, J=9.82 Hz, 1H), 0.47 (d, J=7.93 Hz, 2H), 0.27-0.40 (m, 2H).
Reaction SMILES: [Cl:1]C[C:3]1[N:4]=[CH:5][N:6]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[C:7]=1[CH2:8][CH2:9][CH3:10].[CH3:17][NH2:18]>>[ClH:1].[CH3:17][NH:18][C:3]1[N:4]=[CH:5][N:6]([S:11]([N:14]([CH3:15])[CH3:16])(=[O:12])=[O:13])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1c(CCl)ncn1S(=O)(=O)N(C)C
Reactant: CN
Product: CCCc1c(NC)ncn1S(=O)(=O)N(C)C
Product: Cl

Procedure:
4-(Chloromethyl)-N,N-dimethyl-5-propyl-1H-imidazole-1-sulphonamide (189 mg) was stirred with excess methylamine (33% solution in ethanol; 5 ml) at room temperature under nitrogen for 18 h. The reaction mixture was evaporated under reduced pressure to give the title compound as an oil (167 mg), t.l.c. (System A, 100:10:1) Rf 0.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[NH:3]1.C([Li])CCC.[Br:16][CH:17]([CH3:21])[C:18](Br)=[O:19].P([O-])([O-])([O-])=O>O1CCCC1.CCCCCC>[Br:16][CH:17]([CH3:21])[C:18]([N:3]1[C:2]([CH3:10])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5][C:4]1=[O:9])=[O:19]
Reactant: CC1(C)NC(=O)OC1(C)C
Reactant: CC(Br)C(=O)Br
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Br)C(=O)N1C(=O)OC(C)(C)C1(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 4,4,5,5-tetramethyloxazolidin -2-one (0.30 g; 2.01 mmol) in tetrahydrofuran (2.5 ml), a hexane solution of 1.57 N n-butyl lithium (1.50 ml; 2.3 mmol) was added at 0° C., and after 5 minutes, 2-bromopropionyl bromide (0.54 g; 2.5 mmol) was added thereto and followed by stirring at the same temperature for 10 minutes. A phosphate buffer (pH 7) (1.1 ml) was added thereto to decompose the excess reaction agent, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 5% aqueous solution of sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a residue, which was purified by silica gel column chromatography (benzene→benzene:ethyl acetate=95:5) to give 3-(2'-bromopropionyl)-4,4,5,5-tetramethyloxazolidin-2-one as a colorless solid.
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([NH:35][CH2:36][CH:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1>C(Cl)Cl.O>[Cl:30][C:31]1[CH:41]=[CH:40][C:34]([NH:35][CH2:36][CH:37]([NH:39][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:38])=[CH:33][CH:32]=1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(N)CNc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(CNc1ccc(Cl)cc1)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
1.9 g of N-methylpiperidine was added to a solution containing 3.8 g of N-isopropoxycarbonyl-L-valine dissolved in 80 ml of methylene chloride, at -20° C. After the mixture was stirred for 15 minutes at the same temperature, 2.6 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 3.5 g of 2-(4-chloroanilino)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 3.3 g of the desired product in the form of a white crystal (yield: 47%).
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:20])[CH3:19])[CH:13]=1.[C:22]([O:25][C:26](=[O:28])[CH3:27])(=O)[CH3:23].Cl>>[CH3:19][N:18]([CH3:20])[C:14]1[CH:13]=[C:12]([N:11]([CH3:21])[CH3:10])[CH:17]=[CH:16][C:15]=1[C:22]1([C:5]2[CH:4]=[CH:3][C:2]([N:11]([CH3:12])[CH3:10])=[CH:7][CH:6]=2)[C:23]2[C:27](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:26](=[O:28])[O:25]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1ccccc1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Product: CN(C)c1ccc(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3ccccc32)cc1
Temperature: 95 °C

Procedure:
A mixture of 2-(4-dimethylamino)benzoyl)benzoic acid (26.8 g.), N,N,N',N'-tetramethyl-m-phenylenediamine (16.4 g.) and acetic anhydride (80 g.) was heated (to 95° C.) during one hour, cooled and poured into dilute hydrochloric acid. The resulting mixture was basified. Recrystallization of the resulting solid from a mixture of toluene and hexane afforded 3-(2,4-bis(dimethylamino)phenyl)-3-(4-(dimethylamino)-phenyl)phthalide (I: X = Y4 = (CH3)2N, Y2 = Z4 = Z5 = Z6 = Z7 = H) (m.p. 190°-194° C.).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C@@H:10]1[NH2:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1)=[C:32]=[S:33]>C(#N)C>[CH2:2]([CH:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH:10]1[NH:21][C:32]([NH:31][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1)=[S:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COCOc1ccc(CN=C=S)cc1OC
Reactant: COc1ccc2c(c1)CC[C@H](N)[C@@H]2Cc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(CNC(=S)NC2CCc3cc(OC)ccc3C2Cc2ccccc2)cc1OC

Procedure:
A solution of cis-1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamine hydrochloride (0.306 g, 1.01 mmol), diisopropylethylamine (0.264 mL, 1.51 mmol) and 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene (0.253 g, 1.06 mmol) in acetonitrile (10 mL) was stirred at ambient temperature overnight. The solvent was evaporated in vacuo, and the residue was purified by reverse phase preparative HPLC, on a C18 column eluted with a gradient of 40 to 90% acetonitrile in water with 0.1% TFA, to give the product, 1-(1-benzyl-6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-3-(3-methoxy-4-methoxymethoxy-benzyl)-thiourea, 0.21 g (41%). 1H NMR (CDCl3): δ 1.64 (br s, 1H), 1.85 (m, 1H), 2.04 (m, 1H), 2.63 (m, 1H), 2.82 (m, 2H), 2.98 (m, 1H), 3.33 (m, 1H), 3.49 (s, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 4.32 (br s, 2H), 5.19 (s, 2H), 5.7 (br s, 1H), 6.0 (br s, 1H), 6.64 (m, 3H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H) and 7.11 to 7.28 (m, 5H). MS: m/z 507 (M+H)+.
Reaction SMILES: [C:1]([Cl:4])(=O)C.[NH2:5][C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:4].[CH3:1][O:15][C:14](=[O:16])[C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)[C@H](N)Cc1ccccc1
Product: Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
Anhydrous methanol (50 mL) is taken in a 100 mL 2-necked round bottom flask fitted with a reflux condenser and an additional dropping funnel and cooled to ice temperature. Acetyl chloride (3 mL) is added drop wise through the dropping funnel. After 15 min, D-phenylalanine (3 g, 18.16 mmol) is added and the reaction mixture is refluxed at 70° C. for overnight. The reaction mixture is vacuo dried to obtain D-phenylalanine methylester hydrochloride in quantitative yield and used for further reaction without purification.