Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Na+].[CH:3]1[C:8](O)=[C:7](O)[C:6](O)=[CH:5][C:4]=1[C:12](OC1C=[C:17]([C:23]([O:25][CH2:26][C@H:27]2[O:32][C@@H:31](OC(C3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@H:30]([O:56][C:57]([C:59]3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@@H](OC(C3C=C(O)C(O)=C(OC(C4C=C(O)C(O)=C(O)C=4)=O)C=3)=O)[C@@H]2OC(C2C=C(O)C(O)=C(OC(C3C=C(O)C(O)=C(O)C=3)=O)C=2)=O)=O)C=C(O)C=1O)=O.[CH:125]([CH:127]=[CH2:128])=O>S(=O)(=O)(O)O.O>[CH:127]([C:125]1[CH:12]=[CH:4][CH:3]=[CH:8][C:7]=1[CH:6]=[CH2:5])=[CH2:128].[CH2:59]=[CH:57][O:56][CH2:30][CH2:31][O:32][CH2:27][CH2:26][O:25][CH:23]=[CH2:17]
Reactant: C=CC=O
Reactant: O=C(OC[C@H]1O[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H](OC(=O)c2cc(O)c(O)c(OC(=O)c3cc(O)c(O)c(O)c3)c2)[C@@H]1OC(=O)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1)c1cc(O)c(O)c(OC(=O)c2cc(O)c(O)c(O)c2)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=COCCOCCOC=C
Product: C=Cc1ccccc1C=C
Temperature: 50 °C
Yield: 81.1 %

Procedure:
Sodium chloride (116 g), 4 drops concentrated sulfuric acid and 150 g of water are added to a 1-liter flask containing an efficient two-tiered stirrer, condenser, and nitrogen inlet tube. Polyacrylic acid dispersant, such as 5 gm of Primafloc C-7 available from Rohm and Haas Company, is then added to a solution containing a 0.1 g tannic acid dissolved in 136 g of water. This solution is then added to the stirred flask containing sodium chloride. This aqueous phase is then sparged with nitrogen. In a separate flask, 314 mls. of acrolein is sparged for 20 - 30 minutes with nitrogen. In a separate flask a solution of 29.6 g of divinylbenzene (DVB-81.1% active), 6.0 g of diethyleneglycoldivinylether (DEGDVE), and 9.0 g of Percadox 16 (bis-t-butylcyclohexyl percarbonate) is prepared. This latter solution is then added to acrolein, shaken until homogeneous, and added to the aqueous phase in the reaction flask after the stirrer had been turned off and the nitrogen sparge had been converted to a nitrogen atmosphere. A suspension formed in 20 - 30 minutes on intermittent agitation at 145 rpm. The position of the stirrer blade must be at the interfaces of the two liquid phases. After the dispersion is formed, the reaction mixture is heated to 50°C. and held there with intermittent heating and air cooling for 16 hours. The reaction contents are then cooled to room temperature, the liquid drained, and the resin given three water washes. After washing with methanol, the resin is dried at 75°C. for 16 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2.[CH3:16][C:17](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:18]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:17]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2)(=[O:18])[CH3:16]
Reactant: Nc1ncc2ncn(COCCO)c2n1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.82 g (3.92 mM) of 9-(2-hydroxyethoxymethyl)-2-amino-9H-purine, 48 mg (0.392 mM) of a 4-dimethylaminopyridine and 0.75 ml (7.84 mM) of acetic anhyride in 18 ml of dry dimethylformamide was stirred at room temperature for two days. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate and absorbed on silica gel. The solvent was removed by flash evaporation and the residual powder added to a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0 g of a semicrystalline oil which on recrystallization from benzene-hexane gave analytically pure 9-(2-acetoxyethoxymethyl)-2-amino-9H-purine, mpt. 115°-118° C. An additional crop was obtained from the mother liquor.
Reaction SMILES: [S:1]1[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:5]3[CH2:4][CH2:3][CH2:2][S:1][CH2:8][CH2:7][C:6]=3[C:15]=2[CH:14]=1
Reactant: COc1ccc(NN)cc1
Reactant: O=C1CCCSCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)CCSCCC3
Reaction time: 5 h

Procedure:
A mixture of 14.42g (0.1 mole) of 1-thiacyclooctane-5-one, 17.46g (0.1 mole) of p-methoxyphenylhydrazine hydrochloride and 8.21g (0.1 mole) of anhydrous sodium acetate in 170 ml of acetic acid is refluxed with stirring for five hours under nitrogen. The mixture is cooled and poured into 1 liter of water. On standing there is deposited a solid which after washing with water and recrystallization from methanol, gives 18.1g (74%) of an analytical sample, m.p. 122.5°-123.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.Cl.Cl.[F:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH2:28])[CH2:24]2)=[CH:20][CH:19]=1.C(N(CC)CC)C>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([NH:28][C:2]3[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=3)[CH2:24]2)=[CH:29][CH:30]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Reactant: N[C@@H]1CCN(Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccc(F)cc3)C2)cn1
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
A mixture of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg, 1.41 mmol), (3R)-1-(4-fluorobenzyl)-3-pyrrolidinamine dihydrochloride (565 mg, 2.11 mmol) and triethylamine (928 mg, 9.17 mmol) was stirred at 100° C. for 6 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (35% EtOAc/hexane-50% EtOAc/hexane) to give ethyl (2E)-3-(5-{[(3R)-1-(4-fluorobenzyl)-3-pyrrolidinyl]amino}-2-pyrazinyl)acrylate (245 mg, 47%) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:6]1
Reactant: Fc1cccc(CCBr)c1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3cccc(F)c3)CC1)CC2
Yield: 58.1 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 3-fluorophenethyl bromide (220 mg) were treated as in Example 2 to give the title compound (210 mg) as white needles (yield: 58%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[F:22][C:23]([F:27])([F:26])[CH2:24]O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][O:7][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: OCC(F)(F)F
Reactant: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)c(OCCOCC(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-bromo-5-chloro-4-(4-ethylbenzyl)phenoxy)ethanol (AU) (0.53 g, 1.4 mmol) in anhydrous CH2Cl2 (4 mL), was added 2,2,2-trifluoroethanol (0.43 g, 4.3 mmol) and triphenylphosphine polystyrene resin (0.57 g, 2.2 mmol). The resulting mixture was stirred overnight at room temperature, after which it was heated for 2 h at 45° C. The mixture was absorbed onto Celite and purified using silica gel column chromatography eluting with a gradient of EtOAc in hexanes to give intermediate BR. 1H-NMR (CDCl3, 300 MHz) δ 7.36 (s, 1H), 7.14 (m, 4H), 6.94 (s, 1H), 4.17-4.01 (m, 8H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[Mg+2].[Cl-].[Cl-]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Mg+2]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
The thus formed immobilized enzyme conjugate was packed in a suitable column and a 45% solution of fructose with 5×10-3M MgCl2 was passed over the conjugate while maintaining the temperature at 60° C. for a period of 2 hours. At the end of the 2 hour period the amount of glucose formed and the flow rate were assayed. It was found that the activity of the enzyme was 131 units/gram.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (29.9 g) was dissolved in chloroform (150 ml), triethylamine (32 ml) and p-fluorobenzyl chloride (27.5 ml) were successively added under ice-cooling, and the mixture was stirred overnight. The reaction solution was successively washed with a 20% aqueous solution of sodium hydroxide (150 ml×2) and water (150 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (49.4g) as a yellow oily substance. Yield=94%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:51][C:52]1[CH:53]=[C:54]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([NH2:65])[CH:60]=2)[CH:55]=[CH:56][C:57]=1[CH3:58].C(N(CC)CC)C>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:20])[NH:65][C:61]3[CH:60]=[C:59]([C:54]4[CH:55]=[CH:56][C:57]([CH3:58])=[C:52]([CH3:51])[CH:53]=4)[CH:64]=[CH:63][CH:62]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: Cc1ccc(-c2cccc(N)c2)cc1C
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A mixture of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (50 mg, 0.1415 mmol), 1-(3-(dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (32.55 mg, 0.170 mmol), 1-hydroxybenzotriazole monohydrate (26.01 mg, 0.170 mmol), and 1,2-dichloroethane (2 ml) was stirred at ambient temperature for 30 minutes. To the mixture was added 3′,4′-dimethylbiphenyl-3-amine hydrochloride (39.69 mg, 0.170 mmol) and triethylamine (98.62 μl, 0.707 mmol) and the mixture was stirred for 2 days at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 36 mg of the title compound as a thin film (48%).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:49])[C:23]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH2:29][CH2:28]3)=[O:24])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[NH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH3:49])[C:23]([CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([O:33][C:34](=[O:48])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH2:31][CH2:32]1)=[O:24]
Reactant: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CN(CCCN)C(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To biphenyl-2-ylcarbamic acid 1-(2-{[3-(9H-fluoren-9-ylmethoxycarbonyl-amino)propyl]methylcarbamoyl}ethyl)piperidin-4-yl ester (2.2 g, 3.3 mmol) was added a 10% solution of piperidine (0.31 g, 3.3 mmol) in DCM (3.2 mL) and the resulting mixture was shaken at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 mL). This mixture was washed with water (2×20 mL) and then extracted with ammonium chloride (1 N, 2×20 mL). The layers were separated and DCM was added to the aqueous layer. The aqueous layer was made basic by addition of aqueous potassium hydroxide (1 N) and the layers were separated. The organic layer was washed with aqueous potassium hydroxide (1 N, 2×20 mL) and brine (1×20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.0 g, 66% yield) as a clear oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH:36]1([CH2:39][NH2:40])[CH2:38][CH2:37]1.[BH4-].[Na+]>C(Cl)Cl.CO>[CH:36]1([CH2:39][NH:40][CH2:34][C@@H:10]2[CH2:9][NH:8][CH2:12][C@H:11]2[CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:38][CH2:37]1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Reactant: NCC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNCC2CC2)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), cyclopropanemethylamine (0.652 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 548.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.66 min.
Reaction SMILES: C[Sn]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]#[N:15])[CH:12]=2)[N:7](C2CCCCO2)[N:6]=1)(C)C.Br[C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2.Cl.C(=O)([O-])[O-:35].[K+].[K+]>CN(C)C=O.O.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[C:23]([C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH2:15])=[O:35])[CH:12]=3)[NH:7][N:6]=2)[CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1cnc2ccccc2c1
Reactant: C[Sn](C)(C)c1nn(C2CCCCO2)c2ccc(C#N)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: NC(=O)c1ccc2[nH]nc(-c3cnc4ccccc4c3)c2c1
Temperature: 80 °C
Yield: 41 %

Procedure:
A mixture of the 3-(1,1-dimethyl-1-stannaethyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.250 g, 0.64 mmol), 3-bromoquinoline (0.088 mL, 0.64 mmol) and tetrakis(triphenylphosphine)palladium (0.074 g, 0.064 mmol) in N,N-dimethylformamide (5 ml) was heated at 80° C. for 14 h. The mixture was cooled to room temperature, diluted with water and the filtered solid was dried in the vacuum oven. Purification of the solid by column chromatography (silica gel, 30% ethyl acetate/hexanes) gave an intermediate solid which was dissolved in methanol (30 mL). Aqueous 6 N hydrochloric acid (30 mL) was added and the mixture heated at 45° C. for 4 h. The reaction mixture was poured into water, basified with potassium carbonate and the yellow solid collected by suction filtration. A mixture of this product, methanol (20 mL), aqueous 6 N sodium hydroxide (2 mL) and aqueous 30% hydrogen peroxide (3 mL) was heated at 45° C. for 3 h. Water (30 mL) was added and the solid collected. Purification of the residue by preparative HPLC (20–80% acetonitrile/water) gave the title compound (0.075 g, 41% yield): 1H NMR (DMSO-d6) δ 13.73 (s, 1H), 9.61 (d, 1H), 9.01 (s, 1H), 8.81 (s, 1H), 8.22 (m, 2H), 8.11 (d, 1H), 8.02 (d, 1H), 7.83 (t, 1H), 7.71 (t, 2H), 7.43 (br s, 1H); ES-MS (m/z) 289 [M+1]+.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([OH:26])=O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.CNC>ClCCl.O1CCCC1>[CH:8]1([CH2:14][C:15]([NH:17][CH2:18][CH2:19][S:20][CH2:21][CH:22]([C:27](=[O:34])[C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH2:23][C:24]([N:3]([CH3:4])[CH3:1])=[O:26])=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: O=C(O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)CC(CSCCNC(=O)CC1CCCCC1)C(=O)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (14.7 tL) was added to a solution of 3-{[2-(N-cyclohexylacetylamino)ethylthio]methyl}-4-oxo-4-(3-pyridyl)butanoic acid (44.6 mg) in dichloromethane (1.1 mL) and stirred for 30 min. The solution was cooled to 0° C. and ethyl chloroformate (10.5 μL) was added and stirred for 10 minutes. Dimethylamine in tetrahydrofuran (2M, 53 μL) was added and stirred at room temperature overnight. The solution was concentrated and purified on preparative HPLC (C-18 prep column, 10% to 90% acetronitrile in water both containing 0.1% TFA) to give 6.8 mg of the title compound; ESMS (M+1)+420.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:23])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:4][CH2:5][C@@H:6]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])[C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
To a suitable reactor was added 4a (2 g, 6.18 mmol), CH2Cl2 (20 mL), DMAP (0.15 g, 1.24 mmol), and Et3N (1.37 g, 13.61 mmol) at 20-30° C. under N2. The mixture was cooled to 0-5° C., and MsCl (1.4 g, 12.36 mmol) in CH2Cl2 (3 mL) solution was added at this temperature. The mixture was warmed to 20-30° C. and stirred for 1 hr. H2O (10 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was washed with 20% NaCl aqueous solution (10 mL). The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford 5 (2.8 g) as a yellow solid in quantitative yield.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:18][CH2:19][O:20]CC1C=CC(OC)=CC=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C([O-])(O)=O.[Na+]>ClCCl.O>[Si:1]([O:8][C@@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH2:19][OH:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(COCC[C@H](CCc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](CCO)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
(S)-3-(t-butyl dimethylsilyloxy)-5-(4-methoxy-benzyloxy)-1-phenyl pentane (15 g, 36.2 mmol) was dissolved in a solvent mixture of dichloromethane-water (20:1) (252 ml). DDQ (8.2 g, 36.2 mmol) was added thereto and the mixture was stirred for 30 minutes at room temperature. After completion of the reaction, saturated aqueous NaHCO3 solution (100 ml) was added to the reaction solution to stop the reaction. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give (S)-3-(t-butyldimethylsilyloxy)-5-phenyl-pentan-1-ol (10.6 g, Yield 99%) of a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.ClC1C=C(C=CC=1)C(OO)=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After stirring 30 min, the reaction mixture was washed with 1% Na2CO3 solution (2×75 mL) and brine. The organic layer was then dried over Na2SO4 and concentrated to give 10.6 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as an orange foam that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[Br:10]Br>O1CCCC1.CCCCCC>[Br:10][C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1nc(C(=O)O)cs1
Reactant: BrBr
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(Br)s1
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methyl-thiazole-4-carboxylic acid (2.48 g, 17.32 mmol) in tetrahydrofurane (200.00 ml) was cooled to −78° C. under argon and treated with a 1.6N solution of buthyllithium in hexanes (22.74 ml, 36.38 mmol). The reaction mixture was left to warm to room temperature over 15 min, then cooled again to −78° C. A solution of elemental bromine (3.04 g, 19.05 mmol) in hexane (2.00 ml) was added. The reaction mixture was left to warm to room temperature, then quenched by addition of 1N HCl. The mixture was extracted three times with methylene chloride, and the combined organic layers were dried over sodium sulphate and evaporated. 5-Bromo-2-methyl-thiazole-4-carboxylic acid (3.79 g, 99%) was obtained as a yellow solid, MS (ISP): m/e=220.0, 222.1 (M−H), which was used crude.