Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[N:11][C:4]=2[NH:3]1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]3)=[N:23]2)=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCCl.CO>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([N:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([CH2:36][NH:37][CH2:12][C:10]4[CH:9]=[CH:8][C:5]5[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=5[N:11]=4)[CH2:34][CH2:35]3)=[N:23]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ncc(OCCCN3CCC(CN)CC3)nc2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2ncc(OCCCN3CCC(CNCc4ccc5c(n4)NC(=O)CO5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.5 %

Procedure:
3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (22 mg, 0.12 mmol 1.0 eq) is added at room temperature to a stirred solution of C-{1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-yl}-methylamine (40 mg, 0.12 mmol, 1.0 eq) in 1,2-dichloroethane (2 mL) and methanol (0.5 mL), followed by acetic acid (9 μL, 0.15 mmol, 1.3 eq) and sodium cyanoborohydride (11 mg, 0.15 mmol, 1.3 eq). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×5 mL) and a saturated sodium hydrogen carbonate aqueous solution (5 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 6-[({1-[3-(7-methoxy-quinoxalin-2-yloxy)-propyl]-piperidin-4-ylmethyl}-amino)-methyl]-4H-pyrido[3,2-b][1,4]oxazin-3-one as a white viscous oil (18 mg, 29% yield).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH2:38][C:39](Cl)=[O:40])[CH:32]=[C:33]([N+:35]([O-:37])=[O:36])[CH:34]=1)([O-:28])=[O:27]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:39](=[O:40])[CH2:38][C:31]3[CH:30]=[C:29]([N+:26]([O-:28])=[O:27])[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. α-(3,5-Dinitrophenyl)acetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro- 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-[α-(3,5 -dinitrophenyl)acetyloxy] -2 (1H)-pyrimidinone as the residue.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].[C:14]1([CH3:25])[CH:19]=[CH:18][C:17]([S:20]([O:23]C)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[C:14]1([CH3:25])[CH:15]=[CH:16][C:17]([S:20]([O-:23])(=[O:21])=[O:22])=[CH:18][CH:19]=1.[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N+:8]([CH3:14])=[CH:9]2)([O-:3])=[O:2]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=[N+]([O-])c1cccc2cnccc12
Solvent: CN(C)C=O
Product: C[n+]1ccc2c([N+](=O)[O-])cccc2c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 72 h
Yield: 169.3 %

Procedure:
5-Nitroisoquinoline (25 g) and methyl p-toluenesulfonate (26.8 g) were dissolved in dimethylformamide (80 ml) and allowed to stand at room temperature for three days. If a crystalline cake had not formed at the end of this time, the solution was either seeded or scratched to initiate precipitation of the product. The supernatant was decanted and ethyl acetate was added to this until no more precipitation was evident. This precipitate was collected by filtration and combined with the first precipitate. The product was recrystallized from ethanol-ethyl acetate to yield 43.9 g of yellow crystals, m.p. 144°-144.7°C.
Reaction SMILES: [CH:1]1[C:6](C(O)=O)=[CH:5][C:4]([C:10]2C3C=CC(O)=CC=3OC3[C:11]=2[CH:12]=[CH:13][C:14]([CH:16]=3)=O)=[C:3](C(O)=O)[CH:2]=1.ON1[C:34](=O)[CH2:33][CH2:32][C:31]1=O.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:52]([N:54]([CH2:57]C)[CH2:55][CH3:56])C>CN(C=O)C>[CH3:57][N:54]([CH2:55][CH2:56][CH:31]=[C:32]1[C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:16]=[CH:34][C:33]1=2)[CH3:52]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Reactant: CCN(CC)CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CN(C)CCC=C1c2ccccc2CCc2ccccc21
Reaction time: 17 h

Procedure:
6-Carboxyfluorescein (1.00 g, 2.66 mmol) was dissolved in 8 mL DMF, 306 mg (2.66 mmol) of N-hydroxysuccinimide (HOSu) was added, 549 mg (2.66 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) was added, and the reaction stirred for 17 hours, under N2, in the dark. The reaction was then vacuum filtered, filtrate combined with 784 mg (2.65 mmol) of 2-aminoimipramine (26c), 0.56 mL (4.0 mmol) of triethylamine, and 4.0 mL DMF, and reaction allowed to stir 4 days under N2, in the dark. Reaction solvents were removed in vacuo and residue purified on reverse phase C18 preparative (1 mm) TLC plates, eluting with H2O/THF/HOAc (40/60/0.4) followed by preparative HPLC on a Waters mbondapak C18 column (19 mm×150 mm), eluting with H2O/THF/HOAc (35/65/0.4) at a flow rate of 7.0 mL/minute to yield 410 mg (24%) of the desired tracer (27) as an orange powder; mass spec (FAB) (M+H)+ 654.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CO)OC
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)OC
Yield: 95 %

Procedure:
To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet is added N-Benzyloxycarbonyl-L-proline (3.5 g), dichloromethane (25 mL) and 2,2-dimethoxyethanol (1.8 g). The mixture is cooled using an ice bath (0-5° C.) and DMAP (86 mg) is added. DCC (3.06 g) is added to the mixture over a period of 2 minutes. The resulting precipitate is filtered, washed with heptanes (2×10 mL) and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptanes/ethyl acetate (4:1) as the eluent, and 4.5 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-prolinate was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]1([C@H:16]([N:11]2[C@@H:10]3[C@@H:13]([CH2:14][CH2:15][NH:8][CH2:9]3)[CH2:12]2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](c1ccccc1)N1CC2CCN(C(=O)OC(C)(C)C)CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1C[C@@H]2CCNC[C@@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the minor isomer product of Example 3E (9.3 g, 29.4 mmol) in 40 mL CH2Cl2 at 0° C. was added 20 mL trifluoroacetic acid. The ice bath was removed after the addition and the mixture stirred at ambient temperature for 3 h then was concentrated under reduced pressure and the residue was purified via column chromatography (SiO2, 1% NH4OH: 9% CH3OH: 90% CH2Cl2) to give the title compound. MS (DCl/NH3) m/z 217 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Reactant: C1=COCCC1
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 77.6 %

Procedure:
A round-bottom flask was charged with 4-bromo-6-(trifluoromethyl)-1H-indazole (1.00 g, 3.8 mmol), TsOH monohydrate (27 mg, 0.15 mmol), 3,4-dihydro-2H-pyran (1.59 g, 18.9 mmol), and THF (25 mL). The reaction mixture was degassed with nitrogen and heated under reflux for 18 h, and then the solvent was removed in vacuo. The residue was purified by SiO2 chromatography to afford 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-6-(trifluoromethyl)-1H-indazole (1.03 g, 78%) as a yellow oil. MS (ESI) m/z: 265.2 [(M−THP group)+1]+.
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O.C(OCC)C>CC(C)=O>[O:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1Oc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: O=C1CCCCC1Oc1ccccc1
Reaction time: 4.5 h

Procedure:
2-Phenoxy-cyclohexanol (13.64 g, 0.071 mol) was dissolved in acetone (260 mL), cooled to between 0° C. to 5° C., and Jones Reagent (2 M, 78 mL) was added dropwise. The reaction was stirred for 4.5 hours. The reaction mixture was poured into water (250 mL), and diethyl ether (500 mL) was added. The organic phase was separated from the aqueous phase, then washed with water, dried (over MgSO4), and concentrated to yellow crystals. The crystals were recrystallized from pentane to give 2-phenoxy-cyclohexanone (a compound of general Formula III) (10.22 g, 76%). 1 HNMR (CDCl3): δ7.2 (m, 2H), 7.0 (m, 2H), 6.8 (d, 1H), 4.6 (m, 1H), 2.6 (m, 1H), 2.4 (m, 2H), 2.0-1.8 (m, 5H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:12][CH:11]=1)[CH3:6].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CN(CCOc1ccc(C(=O)CCC(=O)OC(C)(C)C)cc1)Cc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOc1ccc(C(=O)CCC(=O)O)cc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-Butyl 4-[4-(2-(N-(2-fluorobenzyl)-N-methylamine)ethoxy)phenyl]-4-oxobutyrate (Step E, 2.23 g, 5.3 mol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours, and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 92.5:7.5-90:10 spiked with acetic acid) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([OH:30])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17]1.C([Li])CCC.[C:36]([Cl:40])(=[O:39])[CH2:37][CH3:38]>O1CCCC1.O>[ClH:40].[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([O:30][C:36](=[O:39])[CH2:37][CH3:38])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:18][CH2:17]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(Cc2ccccc2C2(O)CCN(CCc3ccccc3)CC2)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)OC1(c2ccccc2Cc2ccc(C)cc2F)CCN(CCc2ccccc2)CC1
Product: Cl
Reaction time: 0.25 h

Procedure:
A solution of 1.4 g of 4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-1-phenethyl-4-piperidinol, Example 11, in 30 ml of tetrahydrofuran is cooled to -60° C. To this cooled solution is added 1.5 ml of n-butyllithium and the resulting solution stirred for 15 minutes. To this solution is added dropwise 0.3 ml of propionyl chloride at this low temperature and after total addition the solution is permitted to reach ambient temperature. The solution is stirred at ambient temperature for 24 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract is dried and filtered and the chloroform evaporated off leaving a white powder. The powder is recrystallized from a methanol-acetone-ether mixture to give the product, mp 195°-197° C. of 4-[α-(2-fluoro-4-methylphenyl)-2-tolyl]-4-propionyloxy-1-phenethylpiperidine hydrochloride.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][CH2:10][CH2:11][C:12](O)=O>Cl>[Cl:9][CH2:10][CH2:11][C:12]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: O=C(O)CCCl
Reactant: Nc1ccccc1N
Agent: Cl
Product: ClCCc1nc2ccccc2[nH]1
Yield: 32.3 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.3 g, 12.0 mmol) and 3-chloropropionic acid (2.0 g, 18.5 mmol) were refluxed in 4N HCl (13 mL) for 16 hours to give the title compound as white solid (700 mg, 32%). 1H NMR (CD3OD) □ 3.35 (t, 2H, J=6.8 Hz), 4.00 (t, 2H, J=6.8 Hz), 7.18–7.25 (m, 2H), 7.49–7.55 (m, 2H); ES-MS m/z 181.0 (M+H).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.C1(C)C=CC=CC=1.CC(C)C(C1C=C([C:45]#[N:46])C=CC=1)=O.C([C:50]1[CH:51]=[C:52](/[C:56](/[CH:62]([CH3:64])[CH3:63])=[CH:57]\[C:58]([O:60][CH3:61])=[O:59])[CH:53]=[CH:54][CH:55]=1)#N.C(C1C=C(/C(/C(C)C)=C/C(OC)=O)C=CC=1)#N>O1CCCC1>[C:45]([C:51]1[CH:50]=[CH:55][CH:54]=[CH:53][C:52]=1/[C:56](/[CH:62]([CH3:63])[CH3:64])=[CH:57]\[C:58]([O:60][CH3:61])=[O:59])#[N:46]
Reactant: CC(C)C(=O)c1cccc(C#N)c1
Reactant: COC(=O)/C=C(\c1cccc(C#N)c1)C(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: COC(=O)/C=C(/c1cccc(C#N)c1)C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C(\c1ccccc1C#N)C(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of bis(2,2,2-trifluoromethyl)(methoxy carbonylmethyl)phosphonate (0.38 ml, 1.8 mmol) in 2.5 ml anhydrous tetrahydrofuran was added a solution of 18-Crown-6 (1.9 g, 7.5 mmol) in 2.5 ml anhydrous tetrahydrofuran. The reaction mixture was cooled to −78° C. under argon to which was added a solution of 0.5M bis(trimethylsilyl)amide in toluene (3.6 ml, 1.8 mmol). The reaction was stirred at −78° C. for 15 minutes to which was added a solution of 3-(2-methylpropanoyl)benzenecarbonitrile in 2.5 ml anhydrous tetrahydrofuran. The reaction was allowed to warm to room temperature and stirred for 48 hours. The reaction was quenched by the addition of 20 ml of a saturated ammonium chloride solution followed by extraction with 2×25 ml diethyl ether. Combined organic layers were washed with 2×25 ml water, 2×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to give a 9:1 mixture of methyl (2Z)-3-(3-cyanophenyl)-4-methylpent-2-enoate and methyl (2E)-3-(3-cyanophenyl)-4-methylpent-2-enoate (420 mg, 120%) as a clear oil which was sufficiently pure to use without further purification. ES-MS (M+H+): 230.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].Br[C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(OCC(F)(F)F)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Cl)c(OCC(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 74.2 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(2,2,2-trifluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (530 mg, 1.43 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (275 mg, 1.57 mmol), K2CO3 (395 mg, 2.86 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.029 mmol) in THF (3 mL) and H2O (3 mL) was heated at 80° C. in a sealed tube for 3 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel elute with PE to give 1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (360 mg; yield 74%) as colorless oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:24]2[CH2:29][NH:28][C:27](=[O:30])[NH:26][CH2:25]2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59]O)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O1CCCC1.C(OCC)(=O)C>[C:50]1([CH2:56][CH2:57][CH2:58][CH2:59][O:15][C:16]2[CH:17]=[C:18]([CH:24]3[CH2:25][NH:26][C:27](=[O:30])[NH:28][CH2:29]3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: OCCCCc1ccccc1
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CNC(=O)NC2)cc1OCCCCc1ccccc1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
Diisopropylazodicarboxylate (1.1 ml, 5.70 mmol, 1.2 eq) was added to a mixture of (1.06 g, 4.75 mmol, 1.0 eq) tetrahydro-5-(3-hydroxy-4-methoxyphenyl)-2(1H)-pyrimidinone, (1.37 g, 5.23 mmol, 1.1 eq) triphenylphosphine, and (714 mg, 4.75 mmol, 1.0 eq) 4-phenyl-1-butanol in 20 ml of anhydrous tetrahydrofuran. After heating to reflux for about 18 hours, the reaction mixture was cooled to room temperature, diluted with 350 ml ethyl acetate, washed twice with 1N NaOH, once with H2O, once with brine, dried over Na2SO4, and concentrated to yield an orange solid. Silica gel chromatography eluting with 4% CH3OH--CH2Cl2 yielded 527 mg of a white solid, which was recrystallized from ethyl acetate to afford 480 mg, 29%, of white needles. M.P.: 142°-143° C. Elemental Analysis Calc'd for C21H26N2O3 : Cal'd: C, 71.17; H, 7.40; N, 7.90. Found: C, 71.12; H, 7.32; N, 7.75.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][CH:15]1[CH2:20][O:19][CH2:18][CH:17]([CH3:21])[NH:16]1.O>C(#N)C>[CH3:14][CH:15]1[N:16]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:17]([CH3:21])[CH2:18][O:19][CH2:20]1
Reactant: CCOC(=O)CBr
Reactant: CC1COCC(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CN1C(C)COCC1C
Temperature: 60 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (0.311 g, 2.25 mmol) and ethyl bromoacetate (0.319 g, 1.91 mmol) was added to the solution of 3,5-dimethylmorpholine (0.2 g, 1.73 mmol) in acetonitrile (4 mL) at room temperature. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was transferred into iced-water and extracted with ethyl acetate (20 mL×3). The combined organic layers was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification (Crude Yield: 54%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[F:9][C:10]1[CH:22]=[C:14]2[C:15](O[C:18](=O)[N:19](C)[C:13]2=[CH:12][CH:11]=1)=[O:16].CS(C)=O>O>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[N:19]([CH3:18])[C:3](=[O:5])[CH:2]3[CH2:6][CH2:7][CH2:8][N:1]3[C:15](=[O:16])[C:14]=2[CH:22]=1
Reactant: Cn1c(=O)oc(=O)c2cc(F)ccc21
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)C2CCCN2C(=O)c2cc(F)ccc21

Procedure:
A mixture of 6.2 g. of L-proline, 10.0 g. of 5-fluoro-N-methylisatoic anhydride and 30 ml. of dimethyl sulfoxide is heated on a steam bath for 6 hours, cooled and then diluted with 100 ml. of water. The reaction mixture is evaporated with benzene and the benzene layer is washed twice with water and concentrated. The residue is dissolved in ether and cooled. The crystals are filtered off and dried in a vacuum oven. The dextrorotatory 7-fluoro-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)dione melts at 131°-132°, [α]D25 + 417° (1.6%, methanol).
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[Br:16]Br>C(O)(=O)C.O>[ClH:1].[Br:16][C:9]1[CH:8]=[CH:7][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:5][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(N2CCNCC2)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 966 mg (4.0 mmol) of 1-(3-Methylphenyl)piperazine dihydrochloride in 9 mL of acetic acid and 1 mL of water at 0° C. was added 640 mg (4.0 mmol) of bromine. After 1 hour, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.37 (d, 1H), 6.85 (s, 1H), 6.76 (d, 1H), 3.37 (m, 8H), 2.17 (s, 3H) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:12][CH2:11][CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of 2-(3-nitrophenyl)ethanol (9 g, 53.8 mmol) in DCM (100 mL) was cooled to 0° C., then pyridine (22.7 g, 287 mmol) was dropwise added to the reaction solution. Then methylsulfonylchloride was added slowly dropwise, followed by stirring at room temperature for one hour. Water was added to terminate the reaction. The aqueous layer was extracted by ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 3-nitrophenethyl methanesulfonate (13 g, yield 98%). 1H NMR: 400 MHz CDCl3 δ 8.13-8.10 (m, 2H), 7.60-7.53 (m, 1H), 7.53-7.47 (m, 1H), 4.48-4.45 (m, 2H), 3.19-3.15 (m, 2H), 2.95 (s, 3H).
Reaction SMILES: [OH-].[K+].O.C(O)C.[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17]CC)=[O:16]>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CCCOc1cccc(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=C(O)CCCOc1cccc(F)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
To a solution of KOH (0.24 g, 4.28 mmol) in mixed solvents of water (3 mL) and ethanol (3 mL) under N2 was added ethyl 4-(3-fluorophenoxy)butanoate (0.30 g, 1.33 mmol) in one portion and the mixture was stirred at 40° C. for 4 h. It was then cooled to rt and 20 mL of DCM was added. The organic layer was washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (0.25 g, 96%).