Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13](N)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.N([O-])=O.[Na+].[Na+].[I-:22]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([I:22])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(I)ccc2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester (18.37 g, 83.02 mmol) was added an aqueous HCl solution (21 mL conc. HCl in 200 mL H2O, 252 mmol)) and the resulting mixture was cooled to 0° C. A solution of NaNO2 (6.02 g in 60 mL H2O, 87.25 mmol) was added and the mixture was allowed to stir at 0° C. for 10 min. A solution of NaI (13.07 g in 60 mL H2O, 87.20 mmol) was added slowly. The reaction mixture became difficult to stir during the addition of NaI. A total of 300 mL of water was added in several portions. After the addition was complete, the reaction was warmed to rt and allowed to stir at rt for 2 h. The mixture was then diluted with CH2Cl2 (800 mL) and water (100 mL). The organic layer was separated, washed with 200 mL of saturated NaHCO3 and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was filtered through a pad of silica gel, washing with EtOAc/hexanes (0% to 10%). The filtrate was then concentrated and the residue was recrystallized from MeOH to give 5-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester as light orange solid. MS (EI): cal'd 332.9 (MH+), exp 333.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:57])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[CH:16][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:14][C:13]=2[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)=[CH:6][C:5]=1[O:55][CH3:56].[OH-].[Na+]>C1COCC1.CCO>[CH3:56][O:55][C:5]1[CH:6]=[C:7]([CH2:10][O:11][C:12]2[C:13]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:52])([F:53])[F:54])[CH:46]=3)=[CH:14][C:15]([C:28](=[O:44])[NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:57])=[O:2]
Reactant: COC(=O)c1ccc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2c(-c3cccc(C(F)(F)F)c3)cc(C(=O)NCCCCCCCCc3ccccc3)cc2-c2cccc(C(F)(F)F)c2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 2-methoxy-4-[5′-(8-phenyl-octylcarbamoyl)-3,3″-bis-trifluoromethyl-[1,1′;3′,1″]terphenyl-2′yloxymethyl]-benzoic acid methyl ester (0.352 g, 0.44 mmol, 1 eq) in THF/EtOH (3/2) (10 mL) was added 1M NaOH (4 mL) and the reaction was stirred at rt overnight. It was then concentrated in vacuo, diluted with H2O, and acidified with 2M HCl to pH 1. It was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane+1% Formic acid) to afford the title compound (0.342 g, 865) as a white foam. 1H NMR (DMSO-d6) δ 12.50 (bs, 1H); 8.59 (t, 1H); 7.99-7.92 (m, 6H); 7.80-7.68 (m, 4H); 7.37 (d, 1H); 7.26-7.10 (m, 5H); 6.38 (s, 1H); 6.30 (d, 1H); 4.21 (s, 2H); 3.58 (s, 3H); 3.26 (dd, 2H); 2.52 (t, 2H); 1.53 (m, 4H); 1.28 (m, 8H); IR (KBr) 3350, 2950, 2850, 1720, 1640, 1620, 1550, 1495, 1475, 1415, 1320, 1160, 1150, 1120, 1095, 1080, 1030 cm−1; mass spectrum [(+)APCI], m/z 778 (M+H)+; Anal. Calcd. for C44H41F6NO5: C, 67.95; H, 5.31; N, 1.80, Found: C, 67.22; H, 5.22; N, 1.74.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Reactant: Cc1ccc(C(=O)O)s1
Product: Cc1ccc(C(=O)NCCS(=O)(=O)NC2CCN(C(C)C)CC2)s1

Procedure:
5-Methyl-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide was prepared by an analogous procedure as described in example 9 starting from 94 mg (1.1 equiv.) 5-methyl-thiophene-2-carboxylic acid and 150 mg (0.60 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA) gave pure 5-methyl-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. The title compound was obtained as its trifluoroacetate in form of a colorless amorphous material, which turned out to be hygroscopic with time.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Br[C:15]1[N:16]=[C:17]([CH:33]2[O:37][CH2:36][CH2:35][O:34]2)[N:18]([CH2:22][C:23]2[C:31]([Cl:32])=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)[C:19]=1[CH:20]=[O:21]>CN(C)C=O>[Cl:32][C:31]1[C:23]([CH2:22][N:18]2[C:19]([CH:20]=[O:21])=[C:15]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:16]=[C:17]2[CH:33]2[O:37][CH2:36][CH2:35][O:34]2)=[CH:24][C:25]2[O:29][CH2:28][O:27][C:26]=2[CH:30]=1
Reactant: O=Cc1c(Br)nc(C2OCCO2)n1Cc1cc2c(cc1Cl)OCO2
Reactant: CCOC(=O)CCCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCSc1nc(C2OCCO2)n(Cc2cc3c(cc2Cl)OCO3)c1C=O
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
3.9 g of ethyl 6-mercaptohexanoate is dissolved in 200 ml of anhydrous dimethylformamide, 1.1 g of sodium hydride at 50% in oil is added and the reaction medium is left for 20 minutes at ambient temperature. Then 7.6 g of the product obtained in Stage 4 above is added, and the whole is left overnight at ambient temperature. The dimethyl-formamide is evaporated off under vacuum, the residue is taken up in 200 ml of saturated ammonium chloride and extraction is carried out with three times 200 ml of methylene chloride. The organic phases are dried, filtered and evaporated to dryness. The residue is impasted in isopropyl ether and filtered. In this way 5.8 g of expected product (solid) is obtained.
Reaction SMILES: C([NH:11][C:12](=[N:47]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.[ClH:58].CO>CC(O)=O.[Pd]>[ClH:58].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:47])=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Reaction time: 4 h

Procedure:
(R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]-arginine amide (5.40 g; 7.10 mmol; from step (f) above) in HOAc (300 mL) was flushed with nitrogen prior to the addition of 10% Pd/C (w/w; 1.10 g). The heterogeneous solution was briefly flushed with hydrogen and then stirred under 1 atmosphere of hydrogen for 4 hours. When the deprotection was complete, as determined by TLC analysis, the solution was filtered through a pad of Celite to remove the catalyst. The filtrate was evaporated at reduced pressure to give the crude product. The crude acetate salt was dissolved in HCl/MeOH, treated with activated carbon, filtered, concentrated, and dried under vacuum at 55-60° C. for 5 hours to give the sub-title compound as an off-white solid (3.47 g).
Reaction SMILES: [CH2:1]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: BrBr
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)C(Br)c1ccccc1
Yield: 99.7 %

Procedure:
196 g (l mole) of phenyl benzyl ketone were suspended in 1 liter of carbon tetrachloride. A solution of 51 ml (1 mole) of bromine in 50 ml of carbon tetrachloride were added dropwise, under irradiation (UV), at a rate such that a steady consumption of bromine took place. The solvent was then distilled off in a water pump vacuum. 274 g (quantitative yield) of ω-bromo-ω-phenyl-acetophenone of melting point 48°-50° C. were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=2[CH:21]=1>>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: N#CCc1ccc(Nc2nc(Cl)ncc2Cl)cc1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccc(CC#N)cc4)n3)cc21

Procedure:
{4-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-acetonitrile was prepared from [4-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one in an analogous manner to Example 1d. White solid 130 mg (96%), MP:163-164, HPLC purity 94%, LCMS: 447.25 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.08-7-11 (m, 3H), 7.01 (s, 1H), 3.84 (s, 2H), 2.67 (bs, 2H), 2.34-2.31 (m, 2H), 2.29-2.18 (m, 2H), 1.58 (s, 2H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[OH-].[K+].I[CH3:15]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH3:11]
Reactant: CI
Reactant: Cc1c[nH]c2ccc(F)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 5-fluoro-3-methyl-indole (CAS: 392-13-2, 2.5 g) in DMF (20 ml) was added potassium hydroxide (1.41 g). The suspension was stirred at rt for 1 h and iodomethane (2.85 g) was added dropwise at 0-5° C. The reaction mixture was stirred at rt for 18 h and concentrated under high vacuum. The residue was quenched with water and extracted with ethyl acetate. The organics were washed, dried and concentrated. The crude residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (2.15 g) as a colorless liquid. MS (EI): 163.1 (M)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:13])[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C(#N)C.S(=O)(=O)(O)O.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:13])[O:11][C:12]=2[CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(-c2cccc(Cl)c2)co1
Reactant: C=CC(=O)OC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: COC(=O)CCc1oc(=O)[nH]c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63 %

Procedure:
To a solution of 4-(3-chlorophenyl)oxazol-2(3H)-one (3.31 g) and acetonitrile (15 mL) was gradually added conc. sulfuric acid (5.01 g) at 0° C. To the reaction mixture was added methyl acrylate (3.05 mL) at 0° C. and the mixture was stirred at room temperature for 5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate-tetrahydrofuran (1:1). The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[4-(3-chlorophenyl)-2-oxo-2,3-dihydro-5-oxazolyl]propionate (3.0 g, 63%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:14]([CH3:24])([CH3:23])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)=[O:16]
Reactant: CC(C)(C)C(=O)N1CCNCC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(C(=O)C(C)(C)C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Stir a solution of 2-chloro-4-methyl-5-nitro-pyridine (0.85 mmol, 0.15 g), 2,2-dimethyl-1-piperazin-1-yl-propan-1-one hydrochloride (0.94 mmol, 0.16 g) and triethylamine (2.12 mmol, 0.3 mL) in a sealed tube at 80° C. overnight. Cool down the mixture to room temperature, add CH2Cl2 and wash with saturated aq. sodium chloride. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 2,2-dimethyl—[4-(4-methyl-5-nitro-pyridin-2-yl)-piperazin-1-yl]-propane-1-one. Subject residue to silica gel chromatography eluting with hexanes/ethyl acetate in a gradient (from 30% up to 60%). MS(ES): m/z=307 [M+H].
Reaction SMILES: [SH:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][CH2:4][CH:3]1[O:6][C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:1][CH2:2]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Reactant: OCC(O)CS
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(CCC(=O)OCC)OC(CO)CS1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 3-mercapto-1,2-propanediol (10.8 g, 0.1 mol), diethyl 4-oxopimelate (23 g, 0.1 mol) and boron trifluoride etherate (2.5 ml) in methylene chloride (300 ml). The crude product was chromatographed on silica gel using 40% ethyl acetate/hexane as eluent to give 14.5 g (45%) of product.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2[CH2:15][S:16][CH2:17][C:4]1=2)[CH3:2].N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH2:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[C:5]2=[CH:15][S:16][CH:17]=[C:4]12)[CH3:2]
Reactant: CCN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 0.246 g. of 4-ethyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one in 2 ml. of dry pyridine is added in portions a total of 0.133 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol-water to give off-white crystals, m.p. 201°-202°C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5]C.C(O)CO.[Na].ClC1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:22])=[O:21])[C:14]=1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>CN(C=O)C>[OH:5][CH2:4][CH2:3][O:2][C:1]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:22])=[O:21])[C:14]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)C=Cc2ccccc2)cc1
Reactant: COCCOC
Agent: [Na]
Solvent: CN(C)C=O
Solvent: OCCO
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Reaction time: 96 h

Procedure:
To a mixture of 1,2-dimethoxyethan (15 ml) and ethyleneglycol (40 ml) was added sodium (298 mg) in small portions. The mixture was stirred until the sodium was completely dissolved. Then DMF (15 ml), followed by 2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (1.0 g) was added. Stirring was continued for 4 days at 100° C. The mixture was evaporated and water (150 ml) was added to the residue followed by addition of acetic acid (1.0 ml). The precipitate was filtered off, washed with water and dried. The crude material was purified by chromatography over silicagel with EtOAc/methanol/aqueous ammonia (25%)=4/1/0.5 to give 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (500 mg). tR=4.54 (LC); M+=412.38 (ES+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3c(c2)CCN3)cc1
Yield: 93.1 %

Procedure:
5-Phenylindole (D29) (0.85 g, 4.4 mmoles) was dissolved in glacial acetic acid (20 ml) and treated with sodium cyanoborohydride (1.34 g, 22 mmoles) at ambient temperature for 2 hrs. Water (100 ml) was added and the mixture basified with sodium hydroxide. Extraction with dichloromethane gave the title compound (D30) (0.8 g, 93%).
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[C:11]([C:13]2[C:17]([CH3:18])=[CH:16][S:15][CH:14]=2)[CH:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]=2[CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[CH2:46]([O:45][C:43]([CH2:42][CH2:41][C:27]1[C:28]([O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:19][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]2[C:17]([CH3:18])=[CH:16][S:15][CH:14]=2)[CH:10]=1)[C:6]([OH:48])=[O:5])=[O:44])[CH3:47]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)OC(C)(C)C)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
3-{6-[2-(2-Ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid tert-butyl ester (1.8 g) was dissolved in a mixture of TFA and dichloromethane (1:1, 20 mL) and stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the crude material was purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (1.2 g, 73% yield).
Reaction SMILES: [CH3:1][O-].[Na+].[SH:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH2:18]C)=[O:16])=[C:8]([C:10]([O:12][CH2:13]C)=[O:11])[N:9]=1.IC>CO>[CH3:1][S:4][C:5]1[N:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([C:15]([O:17][CH3:18])=[O:16])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1
Reactant: CCOC(=O)c1nc(S)n(-c2ccccc2)c1C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1nc(SC)n(-c2ccccc2)c1C(=O)OC
Reaction time: 8 h
Yield: 80 %

Procedure:
Sodium methoxide (1.8 g; 0.033 mol) was slowly added to a suspension of diethyl 2-mercapto-1-phenyl-4,5-imidazoledicarboxylate (10 g; 0.031 mol) in absolute methanol (100 mL) then iodomethane (5 g; 0.035 mol) was added. The mixture was allowed to stir overnight, additional iodomethane (5 g; 0.035 mol) was added and the mixture was stirred for 1 hour. The methanol was removed in vacuo and ice-cold water was added to the residue. The mixture was filtered, the collected solid was washed with water and dried to give 7.6 g (80%) of pure dimethyl 2-(methylthio)-1-phenyl-4,5-imidazoledicarboxylate (mp 121°-122° C).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:33])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:38]1COCC1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([O:33][CH3:38])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[N:16]2[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:11][C:10]=1[O:34][CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: COc1cc(C2(O)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(C2(OC)c3ccccc3C(=O)N2CCc2ccccn2)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of 6 (0.20 g, 0.43 mmol) in dry THF (3 mL) at 0° C., NaH (60%, 0.021 g, 0.86 mmol) was added. After the mixture was stirred for 30 min, Mel (54 μL, 0.86 mmol) was added and stirring was continued overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl (0.5 mL). Solvent was evaporated under reduced pressure and the residue was extracted with CH2Cl2 (2×10 mL). The combined organic layer was washed with H20 (3 mL), brine (3 mL) and then dried over anhydrous Na2SO4. Solvent was evaporated under reduced pressure and the residual red syrup was purified by column chromatography using 35% acetone/hexane as the eluent to provide 7 (0.16 g, 75%) as a light yellow syrup.
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6](Cl)=[O:7])([OH:4])(=[O:3])=[O:2].[NH2:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28].O>CCOCC.C(=O)(O)[O-].[Na+]>[S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([NH:18][CH:19]1[C:25](=[O:26])[N:24]2[CH:20]1[S:21][C:22]([CH3:31])([CH3:30])[CH:23]2[C:27]([OH:29])=[O:28])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: CC1(C)SC2C(N)C(=O)N2C1C(=O)O
Reactant: O=C(Cl)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)SC2C(NC(=O)C(c3ccc4c(c3)CCO4)S(=O)(=O)O)C(=O)N2C1C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride (5 mmole) in 10 ml of ether is added to 5 mmole of 6-amino-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid dissolved in 10 ml of water containing 10 mmole of sodium bicarbonate. The temperature is maintained at about 0° C. during the addition. The reaction mixture is stirred for about 30 minutes at 0° C. The organic phase is separated from the aqueous phase. The pH of the aqueous phase is adjusted to 6.5 to 7.0. The aqueous phase is extracted with ethyl acetate. The ethyl acetate is dried over magnesium sulfate, filtered and evaporated to give the title compound.