Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23]([CH2:24][CH2:25][CH3:26])=[C:22]([C:27]([OH:29])=O)[N:21]=[N:20]3)=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:34]1([NH:36][C:27]([C:22]2[N:21]=[N:20][N:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([NH:10][CH2:9][CH2:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[O:12])=[CH:18][CH:17]=3)[C:23]=2[CH2:24][CH2:25][CH3:26])=[O:29])[CH2:35][CH2:33]1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 182 %

Procedure:
1-(4-{[(3-Phenylpropyl)amino]carbonyl}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (505 mg, 1.29 mmol) obtained in Example 60b), HOBt (87.8 mg, 0.643 mmol, 0.5 eq.) and cyclopropylamine (0.120 ml, 1.67 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 9.0 ml), WSC (302 mg, 1.54 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (35 ml) and washed with 2% aqueous sodium carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (25 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated, and diethyl ether was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (505 mg, 1.17 mmol, 90.7%).
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C:17]#[N:18])=[N:14][CH:15]=1.Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C.CCOCC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([CH2:28][CH2:29][CH2:30][Cl:31])[C:17]#[N:18])=[N:14][CH:15]=1
Reactant: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cccc(C(C#N)(CCCCl)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of hexane washed 60% sodium hydride (0.35 g, 8.6 mmol) in DMF (2 mL) at 0° C. was added a solution of (5-bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile (1.75 g, 5.76 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. 1-bromo-3-chloropropane (0.69 mL, 6.91 mmol) was added and the mixture was stirred at room temperature for 4 h. To the reaction mixture was added H20 (5 mL) and Et2O and the organic layer was washed with brine (5x5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) yielded 1.81 9 of 2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile. 1HNMR (400 MHz, CDCl3) 6 8.65 (s, 1H), 7.76 (dd, 1H), 7.36 (d, 1h), 7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.82 (dd,1H), 4.77 (s, 3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1H), 2.62-2.52 (comp, 1H) 1.89-1.79 (comp, 2H); MS (M+1)378.8, 380.8.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:22][CH2:23]Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>CN(C)C=O>[C:17]([O:22][CH2:23][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CCCC(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 86.9 %

Procedure:
In a 300 cc 4-necked flask equipped with a stirrer, a thermometer and a dropping funnel were placed 80 ml of dimethylformamide. Then, 10.41 g (0.08 mol) of 5-fluorouracil was dissolved in the dimethylformamide and 24.29 g (0.24 mol) of triethylamine was added to this solution. To the mixture was added dropwise over 15 minutes 10.93 g (0.08 mol) of butyryloxymethyl chloride. The mixture was reacted together for 5 hours at room temperature and the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride. The solvent was then distilled from the filtrate and the residue was subjected to a treatment using a column packed with silica gel and a mixture (1:1 in mixing ratio) of benzene and ethyl acetate whereby crude 1-butyryloxymethyl-5-fluorouracil was isolated. This crude product was recrystallized from benzene whereby 16.0 g of pure white crystals having a melting point of 96°~98° C. were obtained in a yield of 86.9%.
Reaction SMILES: [C:1]([C:4]1[C:5](CBr)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[CH:11][C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl[CH2:37]Cl>>[C:1]([C:4]1[C:5]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)=[C:11]([CH3:37])[C:10]([O:24][CH3:25])=[C:9]([O:26][CH3:27])[CH:8]=2)(=[O:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: ClCCl
Product: COc1ccc(-c2c(C(C)=O)c(N3CCOCC3)nc3cc(OC)c(OC)c(C)c23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 72 %

Procedure:
A mixture of 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.5 g), morpholine (1.42 g) and dichloromethane (30 ml) was stirred at room temperature for 15 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-acetyl-4-(3,4-dimethoxyphenyl)-2-morpholino-methyl-6,7-dimethoxyquinoline (1.1 g, 72%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 197°-199° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([OH:8])[CH:7]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].[C:28]([O:37][CH2:38][CH:39]([OH:51])[CH2:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[C:18]([O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:51][CH:39]([CH2:40][O:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:38][O:37][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:24]
Reactant: Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Reactant: CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC
Reactant: O=C(Cl)CCCCC(=O)Cl
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)CCCCC(=O)Oc1cc(Cl)ccc1Oc1ccc(Cl)cc1Cl
Yield: 33 %

Procedure:
Using a similar procedure to that described in Example 6, but using 5-chloro-2-(2,4-dichlorophenoxy)phenol, adipoyl dichloride and 2-hydroxy-3-octanoyloxypropyl octanoate as starting materials, there was obtained 5-chloro-2-(2,4-dichlorophenoxy)phenyl 2-octanoyloxy-1-(octanoyloxymethyl)ethyl adipate as an oil in 33% yield; NMR (CDCL3): 0.85 (6H, br.s, CH3), 1.25+1.65 (24H, br.s, CH2), 2.3 (8H, m, COCH2), 4.2 (4H, m, OCH2), 5.25 (1H, m, CH), 6.6-7.5 (6H, complex, aromatic H)ppm.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]N(C)CCN(C)C.C([Li])CCC.CI.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([CH3:22])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN(C)C
Reactant: COCOc1cccc2cccc(Cc3ccccc3)c12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CI
Product: Cc1ccc2cccc(Cc3ccccc3)c2c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10 g of 8-benzyl-1-methoxymethoxynaphthalene was dissolved in 100 ml of anhydrous ether, followed by the addition of 6.5 ml of tetramethylethylenediamine. 27 ml of a 1.6M solution of n-butyllithium in hexane was dropped into the obtained mixture under cooling with ice. The obtained mixture was stirred at 0° C. for one hour, followed by the dropwise addition of 2.7 ml of methyl iodide. The obtained mixture was stirred at room temperature for one hour and poured into a saturated aqueous solution of ammonium chloride. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was dissolved in 150 ml of acetone, followed by the addition of 60 ml of 6N hydrochloric acid. The obtained mixture was stirred at room temperature for one hour, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The residue was purified by silica gel column chromatography (developer: 3% ethyl acetate/hexane) to give 6 g of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1.[Br-].[CH3:14][CH:15]([CH3:18])[CH2:16][Zn+].CN1C=CN=C1.ClCCl>CN1CCCC1=O>[CH2:14]([C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1)[CH:15]([CH3:18])[CH3:16]
Reactant: N#Cc1ccc2sc(Br)nc2c1
Reactant: CC(C)C[Zn+]
Agent: Cn1ccnc1
Agent: [Br-]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CC(C)Cc1nc2cc(C#N)ccc2s1
Yield: 41.5 %

Procedure:
Heat 2-bromo-benzothiazole-5-carbonitrile (0.3 g, 1.26 mmol) in 1-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide (5 mL, 2.5 mmol, 0.5M solution in THF), N-methylimidazole (0.15 g, 1.88 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20.5 mg, 0.025 mmol) at 80° C. for 3 h. Cool the mixture and partition between diethyl ether and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient) to give the desired intermediate (113 mg, 42%). MS (EI) m/z: 216 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)[CH:3]=1.[S:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1>CO.C(Cl)Cl>[C:18]1([C:4]2[CH:3]=[C:2]([C:27]3([OH:30])[CH2:28][CH2:29][S:24][CH2:25][CH2:26]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: O=C1CCSCC1
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(Br)cc2C2=CCCCC2)n1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3(O)CCSCC3)cc2C2=CCCCC2)n1
Yield: 62 %

Procedure:
The title compound was prepared by the procedure of Example 11 using 4-cyano-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the previous step, 120 mg, 0.323 mmol) and tetrahydro-thiopyran-4-one (188 mg, 1.62 mmol). Silica gel chromatography (1-3% MeOH/DCM) afforded the title compound (82.3 mg, 62%) as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.56 (s, 1H), 9.66 (s, 1H), 8.29 (d, 1H, J=8.6 Hz), 7.74 (d, 1H, J=2.5 Hz), 7.42 (dd, 1H, J=8.6, 2.3 Hz), 7.33 (d, 1H, J=2.3 Hz), 5.86 (m, 1H), 3.22 (m, 2H), 2.46-2.54 (m, 2H), 2.22-2.33 (m, 4H), 2.16-2.22 (m, 2H), 2.01-2.09 (m, 2H), 1.73-1.89 (m, 5H). Mass spectrum (ESI, m/z): Calcd. for C22H24N4O2S, 409.2 (M+H). found 409.1.
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1.[BH4-].[Na+]>CO>[I:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2c(CO)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3-necked 2-L round-bottom flask is equipped with an overhead mechanical stirrer and nitrogen flow is maintained. The flask is charged with 7-iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (105 g, 232 mmol), as prepared above, as a suspension in 700 mL of methanol. The mixture is cooled to 0° C., then sodium borohydride (8.76 mmol) is added in three portions over 15 min. The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is mostly removed in vacuo and the resultant residue is treated with 2.5 L of water and extracted with methylene chloride (4×1.5 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant solid residue is successively treated with 300 mL of methylene chloride and 300 mL of MeOH-EtOAc (1:1). The mixture is swirled at 0° C. for 30 min. The precipitate is filtered by suction, washed with 500 mL of hexane and dried in vacuo at 30° C. yielding [7-iodo-9-(4-methylpiperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as an off-white powder: mp 201-203° C. (dec.). 1H NMR (CDCl3, 200 MHz): d 2.26 (s, 3H), 2.62 (m, 8H), 4.02 (s, 2H). 4.39(s, 4H), 4.93 (m, 2H), 6.05 (br. s, 1H), 7.49 (s, 1H), 7.51 (s, 1H). HRMS (EI+): Calculated for C18H22N3O3: 455.0706. Found: 455.0699.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:5][C:4]=2[N:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([N:28]1[CH2:29][CH2:30][CH:25]([O:24][C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:13]([CH2:20][O:21][CH2:22][CH3:23])=[N:12][C:11]=4[C:2]([NH2:1])=[N:3][C:4]=3[CH:5]=2)[CH2:26][CH2:27]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOCc1nc2c(N)nc3cc(OC4CCNCC4)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OC4CCN(C(C)=O)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 16 h

Procedure:
1-[4-Amino-2-(ethoxymethyl)-7-(piperidin-4-yloxy)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (from Part A) was slurried in dichloromethane (11 mL). Acetic anhydride (0.105 mL, 1.03 mmol) was added and the reaction was stirred for 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-25% CMA in chloroform). The resulting solid was covered with diethyl ether for one week. Filtration of the solid provided 0.130 g of 1-[7-[(1-acetylpiperidin-4-yl)oxy]-4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as red-tan crystals, mp 162-164° C.
Reaction SMILES: ClC1C=CC=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].C(N(CC)CC)C>CN(C=O)C>[C:5]([OH:7])(=[O:6])[CH3:4].[C:5]([O:7][C:8](=[O:9])[CH3:3])(=[O:6])[CH3:4]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)O
Product: CC(=O)OC(C)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
The procedure of Example 1 was repeated except that there was employed 3.0 parts of 4,4'-diphenyletherdithiol, 4.68 parts of 3-chlorophthalic anhydride, 2.85 parts of triethylamine and 38 parts of anhydrous DMF. The mixture was stirred at 50°C. for 3 hours to give a product which after acetic acid/acetic anhydride treatment consisted of a 93% yield of product. Recrystallization of this material from toluene/acetic anhydride gave a product in 87% yield, mp 224°-228°C. Based on the method of preparation the product was a thioetherdianhydride of the formula ##SPC14##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20]O>>[CH3:17][C:18]([CH3:22])=[CH:19][CH2:20][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CC(C)=CCO
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: CC(C)=CCOC(=O)[C@H](C)NC(=O)Cc1cccc(Cl)c1

Procedure:
Following General Procedure C above and using N-(3-chlorophenylacetyl alanine (from Example D above) and 3-methylbut-2-en-1-ol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 30% EtOAc/hexane as the eluant.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[I:26][C:27]1[CH:28]=[C:29]([CH2:33][NH2:34])[CH:30]=[CH:31][CH:32]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:34][CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([I:26])[CH:28]=3)=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: NCc1cccc(I)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cccc(I)c3)cn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A mixture of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (2.00 g, 5.82 mmol), (3-iodophenyl)methanamine (1.00 mL, 7.20 mmol), N-methyl morpholine (2.00 mL, 18 mmol), EDCl (1.2 g, 5.9 mmol), and HOBT (455 mg, 2.91 mmol) in THF (30 mL) was stirred at room temperature overnight. The reaction was diluted with EtOAc (50 mL). The organic layer was washed with saturated aqueous solution of NH4Cl (50 mL), saturated aqueous solution of NaHCO3 (50 mL), and brine (50 mL), dried over Na2SO4 and concentrated to dryness. The residue was purified by flash column chromatography (0-50% EtOAc in Heptanes) to afford (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(3-iodobenzyl)pyrimidine-5-carboxamide (2.39 g, 74%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 2H), 7.69 (m, 1H), 7.64 (m, 1H), 7.32 (m, 1H), 7.10 (t, 1H), 6.98 (m, 2H), 6.88 (m, 2H), 6.13 (t, 1H), 4.58 (d, 2H), 4.48 (dd, 1H), 4.25 (m, 1H), 4.18 (m, 1H), 4.01 (m, 2H), 3.77 (dd, 1H), 3.64 (m, 1H), 2.13 (m, 1H), 1.97 (m, 2H), 1.59 (m, 1H), 1.39 (t, 3H). MS (ES+) 559.2 (M+H).
Reaction SMILES: [Li+].[Cl-:2].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2([CH3:16])[O:15][CH:10]2[C:11]([O:13][CH3:14])=[O:12])[CH:4]=1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:2][C:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)([CH3:16])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: [Cl-]
Reactant: COC(=O)C1OC1(C)c1cccnc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(O)C(C)(Cl)c1cccnc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
0.8 g (20 mmol) of LiCl is dissolved in 100 ml of absolute tetrahydrofuran (THF), the solution is cooled to -20° C., and 20 ml of titanium tetrachloride (1M in dichloromethane) are added dropwise. After the mixture has been stirred for 30 minutes at -20° C., it is cooled to -78° C., and 3.8 g (20 mmol) of methyl 3-(3-pyridyl)-2,3-epoxybutyrate in 50 ml of THF are added dropwise. After the mixture has warmed to room temperature, stirring is continued for 6 hours, the solvent is distilled off, and the residue partitioned between ethyl acetate and water.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[S:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>CC(C)=O.O>[Br-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)[CH2:2][S+:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCSC1
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)C[S+]2CCCC2)cc1
Product: [Br-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a solution of 2-bromo-4′-methylacetophenone (19.18 g, 90 mmol) in 120 mL of acetone and 4.9 mL of water at 0° C. was added tetrahydrothiophene (15.87 g, 180 mmol) dropwise. The resulting mixture was stirred at 0° C. for 1 hour before solid precipitated and was then stirred at room temperature for 1 hour. The resulting crude product was filtered through glass frit as solid and was washed by 100 mL of cold acetone. The crude product was recrystallized by 150 mL of ethanol to afford 19.8 g pure product at a yield of 73%. 1HNMR, d6-DMSO: 7.92 (d, 8.0 Hz, 2H), 7.43 (d, 8.0 Hz, 2H), 5.39 (s, 2H), 3.57 (m, 4H), 2.42 (s, 3H), 2.27 (m, 2H), 2.19 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[C:16]1[CH:21]=CC(S(Cl)(=O)=O)=[CH:18][CH:17]=1.NC1C(C)=CC=CC=1>ClCCl.C([O-])([O-])=O.[K+].[K+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:14]2[CH:18]=[CH:17][CH:16]=[CH:21][C:13]=2[CH3:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1N
Product: Cc1ccccc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
The title compound is analogously synthesized as described for 1-(4-bromo-benzenesulfonyl)-azetidine (compound C3) from 1.28 g of 4-bromo-benzenesulfonyl chloride, 643 mg of commercially available o-toluidine in 20 ml of dichloromethane and 10 ml of K2CO3 solution. Purification by chromatography on flash silica gel (eluent: neat dichloromethane) affords 830 mg of the title compound as colorless, amorphous solid of m.p. 114° C. GC-MS: 327.0 (MH+). TLC: Rf=0.58 (neat dichloromethane).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)=[O:28])[CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:24]([O:26][C:27]([C:29]1[N:30]=[C:31]([NH:34][C:8](=[O:9])[CH:7]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[S:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1csc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-phenoxy-phenyl)-propionic acid (prepared in Example 12A, 767 mg, 2.47 mmol) in methylene chloride (20 mL) at 25° C. was treated with 2-amino-thiazole-4-carboxylic acid ethyl ester (553 mg, 3.21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.64 g, 3.71 mmol), and triethylamine (1 mL, 7.41 mmol). The resulting reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and then extracted with methylene chloride (3×15 mL). The combined organic extracts were washed with a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded 2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazole-4-carboxylic acid ethyl ester (564 mg, 49%) as a white foam: FAB-HRMS m/e calcd for C26H28N2O4S (M+H)+ 465.1848, found 465.1831.