Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[C:28]([O:35][CH3:36])=[N:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.IC1C=NC(OC)=NC=1OC>>[CH3:34][O:33][C:30]1[N:29]=[C:28]([O:35][CH3:36])[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)=[CH:32][N:31]=1
Reactant: COc1ncc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)c(OC)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COc1ncc(I)c(OC)n1
Product: COc1ncc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c(OC)n1
Yield: 83 %

Procedure:
2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(2,4-dimethoxypyrimidin-5-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 5-iodo-2,6-dimethoxypyrimidine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (85 mg, 83%): 1H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 7.34 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.14 (m, 3H), 4.85 (dd, 1H, J=7.4, 5.9 Hz), 4.13 (s, 3H), 4.05 (s, 3H), 2.59 (t, 2H, J=7.8 Hz), 1.93 (m, 2H), 1.60 (m, 2H), 1.41 (m, 4H), 0.89 (s, 9H), 0.09 (s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.4, 164.3, 154.1, 143.9, 142.7, 128.3, 128.1, 125.5, 125.2, 104.9, 68.5, 55.0, 54.4, 36.3, 35.8, 31.3, 29.1, 25.6, 25.6, 25.0, 18.1, −5.0, −5.2.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[CH2:15][N:14]3[CH2:16][CH2:17][NH:18][CH2:19][C@H:13]3[CH2:12][N:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[N:28]1([C:33]2[N:38]=[CH:37][C:36]3[CH:39]([C:42](O)=[O:43])[CH2:40][CH2:41][C:35]=3[CH:34]=2)[CH:32]=[N:31][N:30]=[N:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[N:28]1([C:33]2[N:38]=[CH:37][C:36]3[CH:39]([C:42]([N:18]4[CH2:17][CH2:16][N:14]5[CH2:15][C@@H:10]([C:5]6[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[C:4]=6[CH3:27])[N:11]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:12][C@@H:13]5[CH2:19]4)=[O:43])[CH2:40][CH2:41][C:35]=3[CH:34]=2)[CH:32]=[N:31][N:30]=[N:29]1
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ncc21
Reactant: Cc1c([C@@H]2CN3CCNC[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c([C@@H]2CN3CCN(C(=O)C4CCc5cc(-n6cnnn6)ncc54)C[C@H]3CN2C(=O)OC(C)(C)C)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,9aS)-tert-butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate [I-18A](250 mg, 0.668 mmol) and 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid [I-65] (201 mg, 0.868 mmol) in DMF (4 mL) was added HATU (381 mg, 1.00 mmol) followed by addition of diisopropylethylamine (350 μL, 2.00 mmol). The resulting solution was stirred at rt for 1 h. Ethyl acetate (100 mL) was added and the mixture was washed with saturated sodium bicarbonate (3×100 mL), dried over sodium sulphate, concentrated and the residue was purified by preparative TLC eluting with 10% methanol/methylene chloride to give the title compound. LC/MS: (M+1)+: 588.2.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][Cl:12]>C1COCC1.O>[Cl:12][CH2:11][CH2:10][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: Ic1c[nH]cn1
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ClCCn1cnc(I)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a stirred solution of 4-iodoimidazole (8.8 g, 45.4 mmol) in THF (200 mL) at 0° C. under nitrogen was added portion-wise NaH 60% (1.99 g, 49.9 mmol). After 15 min, 1-bromo-2-chloroethane (4.53 mL, 54.4 mmol) was added at 0° C. The reaction mixture was heated at 60° C. for 20 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/AcOEt: 0/100 to 5/95 over 20 CV), to afford crude 1-(2-chloroethyl)-4-iodo-1H-imidazole not shown in the scheme 57 (7 g, 27.26 mmol, 60% yield) as colorless oil. MS (m/z): 256.83 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Yield: 78 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3,3-dimethyl-butyryl chloride (0.18 mmol, 24 mg) and triethylamine (0.63 mmol, 88 L) were dissolved in DMF and microwaved at 80° C. for 5 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvents in vacuo provided Compound A3 as a yellow solid (46 mg, 78%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.98 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 5.44 (heptet, 1H), 3.71 (m, 1H), 3.48 (m, 3H), 2.75 (s, 3H), 2.11 (quartet, 2H), 1.76 (m, 4H), 0.85 (s, 9H). LCMS (ESI), m/z 492.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19]O)[N:10]=2)=[CH:4][CH:3]=1.CS([Cl:25])(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:25][CH2:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]1[O:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[N:10]2
Reactant: Cc1ccc(CNc2ccc3c(CO)cccc3n2)o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CNc2ccc3c(CCl)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{2-[(5-Methyl-furan-2-ylmethyl)-amino]-quinolin-5-yl}-methanol (example 41, step A, 70 mg, 0.261 mmol) was dissolved in 2 mL tetrahydrofurane and methanesulfonyl chloride (34 mg, 0.297 mmol) and N,N-diisopropyl ethyl amine (41 mg, 0.318 mmol) were added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated off. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). (5-Chloromethyl-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine was obtained as a brown solid (59 mg, 79%), MS: m/e=287.0 (M+H+).
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[NH2:7].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12]>CCO>[NH2:7][C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[NH:8][C:11](=[O:12])[C:10]([F:17])([F:16])[F:9]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Product: N[C@H]1CCCC[C@H]1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
cis-Cyclohexane-1,2-diamine (5.00 g, 43.9 mmol, 1.00 eq) was charged to a 250 mL three-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Ethanol (50 mL) was added and the solution was cooled to <0° C. using an ice-brine bath. A solution of ethyl trifluoroacetate (6.23 g, 1.00 eq) in EtOH (25 mL) was added via a syringe pump over a one hour period. Once the addition was complete, the cooling bath was removed and the solution was slowly warmed to RT and stirred for 3.5 hours to afford the title compound in EtOH. Half (41 mL, about 21.9 mmol) of the total solution (about 82 mL) was carried into the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:24][O:23][C:21]([C:20]1[CH:25]=[CH:26][C:17]([CH2:15][NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:18][CH:19]=1)=[O:22]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CNCC2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 45.9 %

Procedure:
A solution of 1,1-dimethylethyl 2-(aminomethyl)-1-pyrrolidinecarboxylate (1000 mg, 5 mmol) and methyl 4-formylbenzoate (820 mg, 5 mmol) in dichloroethane was stirred as acetic acid (450 mg, 7.5 mmol) and sodium triacetoxyborohydride (1271 mg, 6 mmol) were added sequentially at ambient temperature. After stirring at ambient temperature for 17 hours, treated with a saturated aqueous solution of sodium bicarbonate and extracted with EtOAc. The combined organic extracts were dried and concentrated. Purification by flash chromatography afforded 1,1-dimethylethyl 2-[[[[4-(methoxycarbonyl)phenyl]methyl]amino]methyl]-1-pyrrolidinecarboxylate (800 mg), 1H NMR (CDCl3) 7.98 (d, 2H), 3.37 (d, 2H), 3.91 (s, 3H), 3.82 (s, 2H), 3.36 (m, 2H), 2.72 (m, 1H), 1.82 (m, 3H), 1.44 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[CH3:17]>CO.[Pd]>[F:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(C)=Cc1cc(C)c(F)c(C)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(C)Cc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 88 %

Procedure:
To a solution of Ethyl 3-(4-fluoro-3,5-dimethylphenyl)-2-methylacrylate (0.190 g, 0.855 mmol) in 10 mL of MeOH, was added Pd (10 wt % on activated carbon, 0.038 g). After stirring at room temperature under H2 (1 atm) for 40 h, the reaction mixture was filtered through a pad of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification (0.138 g, 88% yield). LC-MS: tR=10.9 min; m/z 239 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH2:19][OH:20])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>ClCCl>[C:30]([O:20][CH2:19][C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])([CH2:15][CH2:16][CH:17]=[CH2:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCCC(CO)(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCCC(COC(C)=O)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of the ethyl 2-(tert-butoxycarbonylamino)-2-(hydroxymethyl)hex-5-enoate (10.0 g, 35 mmol) and dimethylaminopyridine (4.48 g, 35 mmol) in dichloromethane (100 mL) was treated with acetic anhydride and stirred at room temperature overnight. The solution was concentrated and the resulting residue purified using a combiflash system (89 g column, eluting with 20-50% ethyl acetate in heptanes) to give ethyl 2-(acetoxymethyl)-2-(tert-butoxycarbonylamino)hex-5-enoate (10 g, 80%). 1H NMR (CDCl3) δ 5.78-5.68 (m, 1H), 5.55 (bs, 1H), 5.03-4.93 (m, 2H), 4.73 (d, J=11.0 Hz, 1H) 4.32 (d, J=11.0 Hz, 1H,), 4.20 (q, J=7.2 Hz, 2H), 2.36 (m, 1H), 2.07-2.05 (m, 1H), 2.02 (s, 3H), 1.89-1.75 (m, 2H), 1.43 (m, 9H), 1.27 (t, J=7.2 Hz, 3H). MS found for C16H27NO6 m/z[330(M+1)].
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH3:14])[CH:5]=[C:6]([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11].[CH2:15](Br)[CH3:16]>C1COCC1>[CH2:15]([O:3][CH:4]([CH3:14])[CH:5]=[C:6]([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH3:16]
Reactant: CCBr
Reactant: CC(C)=CCCC(C)=CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)C=C(C)CCC=C(C)C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
THF (500 mL) and sodium hydride (60%, 52 g, 1.3 mol) were charged to a flame dried 2 L reaction flask equipped with a thermometer, a mechanical stirrer, a condenser, and an addition funnel. 8-Hydroxy-2,6-dimethyl-nona-2,6-diene (obtained as detailed above) was added dropwise while allowing the temperature to rise no higher than 50° C. After the addition was completed, the reaction mixture was aged for 1 hour. Ethyl bromide (142 g, 1.3 mol.) was added dropwise for over 2 hours. The reaction mixture was then heated to 60° C. and aged until the conversion rate was shown to be over 90%. The reaction mixture was cooled to lower than 30° C. and quenched by the slow addition of HCl (pH<5, 10%). The layers were split. The aqueous phase was extracted three times with toluene (100 mL). The extracts were added to the crude reaction mixture, which was then washed with saturated sodium bicarbonate followed by saturated salt solution and dried over anhydrous sodium sulphate. The crude reaction mixture was concentrated. The solvents were recovered via a rotary evaporator. Fractional distillation provided the compound 8-ethoxy-2,6-dimethyl-nona-2,6-dien with a boiling point of 125° C. at a pressure of 4.5 mmHg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.CC1C([N+]([O-])=O)=CC=CC=1CC(Cl)=O.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:36]([CH2:37][CH2:38][CH3:39])[CH2:33][CH2:34][CH3:35])=[O:14]
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reactant: CCCNCCC
Agent: Cc1c(CC(=O)Cl)cccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C

Procedure:
The process as shown above comprises conversion of 2-methyl-3-nitro phenyl acetic acid (II) with thionyl chloride to 2-Methyl-3-nitro-phenylacetyl chloride (III), which upon reaction with Di-n-propyl amine (DPA) gives 2-Methyl-3-nitro phenyl-N,N-di-n-propyl acetamide (IV) in syrup form. This intermediate (IV) is further reduced with Borane/THF and subsequent treatment with HCl/NaOH to give 2-Methyl-3-nitro phenyl ethyl-N,N-di-n-propyl amine (V). Further, compound (V) is treated with Na metal, Ethanol and diethyl oxalate to obtain Ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate (VI), which is further treated with hydrogen peroxide , NaOH and HCl and converted to 6-(2-Di-n-propylaminoethyl)-2-nitro phenyl acetic acid hydrochloride (VII). This intermediate is reduced with palladium/carbon to give Ropinirole hydrochloride (Ia).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[NH:17][CH3:18].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([N:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH3:18])=[O:9]
Reactant: CNc1ccccc1OC
Reactant: O=C(O)c1cc(Br)c(Cl)cc1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccccc1N(C)C(=O)c1cc(Br)c(Cl)cc1O
Temperature: 60 °C
Yield: 44.7 %

Procedure:
Alternatively, a mixture of 5-bromo-4-chloro-2-hydroxybenzoic acid (5 g, 19.9 mmol), 2-methoxy-N-methyaniline (3.13 g, 22.9 mmol) and P2O5 (5.36 g, 37.8 mmol) in anhydrous xylene was heated at 60° C. for 2 hrs and then refluxed for 17 hrs. The mixture was concentrated and purified via silica gel flash column chromatography eluted with ethyl acetate in hexane (20%) to give 5-bromo-4-chloro-2-hydroxy-N-(2-methoxy-phenyl)-N-methyl-benzamide (3.3 g).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:36])[CH3:35])[CH:28]=2)[CH2:21]1)(=O)=O.C(#N)C>>[Cl:45][C:40]1[CH:39]=[C:38]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:37])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH:34]([CH3:35])[CH3:36])[CH:28]=3)[CH2:21]2)[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: CC(C)Oc1cccc(CC(=O)N2CC[C@](CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)c1
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(=O)N2CC[C@@](CCN3CCN(C4CCCCC4)CC3)(c3ccc(Cl)c(Cl)c3)C2)c1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl)pyrrolidine (3.17 g), prepared as described, Supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:16]=1[OH:29].O1CCOCC1>N1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:14][C:15]2[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:18]=[CH:17][C:16]=2[OH:29])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCCCCCc1ccc(O)c(N)c1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc(O)c(NC(=O)c2ccc(OC(C)=O)cc2)c1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
In a 20 ml-round-bottomed flask, 2.90 g (16.1 mM) of 4-acetoxybenzoic acid and 3.7 ml of thionyl chloride were placed. To the mixture, two drops of N,N-dimethylformamide was added at room temperature under stirring, followed by heat-refluxing for 20 minutes under stirring. After the reaction, dry benzene was added to the reaction mixture, followed by distilling-off of excessive thionyl chloride together with benzene. The above operation was repeated two times to obtain 4-acetoxybenzoic acid chloride. Then, in a 100 ml-round-bottomed flask, the above-prepared 4-acetoxybenzoic acid chloride, 3.10 g (15.1 mM) of 2-amino-4-octylphenol and 40 ml of dioxane were placed and heated. To the mixture, 5.5 ml of pyridine was added dropwise at 80°-84° C. under stirring, followed by further stirring for 20 minutes at 85°-88.5° C. After the reaction, the reaction mixture was cooled on an ice bath and poured into about 200 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 4.10 g of 2-(4-acetoxybenzoylamino)-4-octylphenol (Yield: 70.8%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19]([CH3:24])([CH2:22]O)[CH2:20][OH:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[OH:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]2[O:21][CH2:20][C:19]([CH3:24])([CH3:22])[CH2:18][O:9]2)=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(CO)CO
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)OC1

Procedure:
A solution of 46.9 parts of 3,5-di-tert.butyl-4-hydroxybenzaldehyde, 21 parts of 2,2-dimethyl-1,3-propane diol and 0.5 parts of 4-toluene-sulphonic acid hydrate in 300 parts of toluene is raised to boiling temperature and reacted with removal of the water of reaction in a separator. After reaction for 6 hours, 85 parts of ethyl acetate are added. The reaction solution is dried over potassium carbonate and the solvent distilled, after which 60 parts of the crude product are obtained. This is recrystallized from hexane to give 2-(4'-hydroxy-3',5'-di-tert.butyl phenyl)-5,5-dimethyl-1,3-dioxane of formula IV, ##SPC3##
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:9]2[C:5](=[CH:6][N:7]([C:12]3[CH:25]=[CH:24][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=3)[N:8]=2)[CH:4]=1.BrB(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:11]=[CH:10][C:9]2[C:5](=[CH:6][N:7]([C:12]3[CH:13]=[CH:14][C:15]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:24][CH:25]=3)[N:8]=2)[CH:4]=1
Reactant: COc1ccc2nn(-c3ccc(OC[C@H](C)NC(C)=O)cc3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)COc1ccc(-n2cc3cc(O)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a solution of N-{(1S)-2-[4-(5-methoxy-2H-indazol-2-yl)phenoxy]-1-methylethyl}acetamide (70 mg) in dichloromethane (3 mL) was added dropwise a dichloromethane solution (1.0 M, 0.83 mL) of tribromoborane under ice-cooling, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:34])[C:28]2[S:33][CH:32]=[CH:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:34])[CH:28]5[S:33][CH:32]=[CH:31][CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: O=c1[nH]c(CCl)nc2ccsc12
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5C=CSC5C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 91.2 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 2-chloromethyl-3H-thieno[3,2-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C24H26N4O4S 466.5632. found (ESI, [M+H]+) 467.1740. 1H NMR (400 MHz, MeOD) δ ppm 1.65-1.92 (m, 4H) 2.06-2.29 (m, 2H) 2.48-2.62 (m, 1H) 2.78-2.89 (m, 1H) 2.89-3.00 (m, 1H) 3.09-3.18 (m, 1H) 3.34-3.53 (m, 4H) 3.55-3.65 (m, 1H) 3.68-3.77 (m, 1H) 4.23-4.32 (m, 1H) 4.60-4.69 (m, 1H) 6.97 (d, J=9.03 Hz, 2H) 7.17-7.24 (m, 1H) 7.73-7.81 (m, 1H) 7.96 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=2.77 min