Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.CN(C)CCN(C)C.[Li]CCCC.CN(C)[CH:38]=[O:39]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:38]=[O:39])[N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a mixture of 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (5 g, 20 mmol) in THF (100 mL) at −78° C. was added tetramethylethylenediamine (3.5 mL, 23 mmol) followed by 2.5 M of n-BuLi (9.3 mL, 23 mmol) dropwise. The reaction was stirred at −78° C. for 1 hour and then N,N-dimethylformamide (2.4 mL, 31 mmol) was added, continue stirred for 1 hours at −78° C. The reaction was quenched with water and extracted with EtOAc. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated. The crude material was triturated with EtOAc to give pure 2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-8-carbaldehyde as a white solid (4.5 g, 80% yield). LC/MS (ESI+): m/z 353 (M+H)
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13].CC(C)([O-])C.[K+].C1COCC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2cccc3c2n1CC=C3
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reaction time: 0.17 h

Procedure:
A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. Heterocyclic Chem., 19, 83749 (1982), 1.0 g, 5.8 mmol) in DMF (10 ml) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at 0°. After 1 hr, the mixture is partitioned with methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) L 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[O:27].CCN(CC)CC>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25][C:26](=[O:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1c(Cl)cccc1Cl
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a mixture of tert-butyl 4-amino-3-methylphenylacetate (1.88 g, 8.51 mmol), 2,6-dichlorophenyl isocyanate (1.60 g, 8.51 mmol) in THF (40 ml) was added Et3N (0.24 ml, 1.70 mmol) at room temperature. After 3 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2,6-dichlorophenyl)ureido]-3-methylphenylacetate (2.58 g, 74%) as a colorless powder. mp 243-244° C. (dec.); 1H-NMR (CDCl3) δ1.45 (s, 9H), 2.30 (s, 3H), 3.49 (s, 2H), 6.24 (s, 2H), 7.12-7.16 (m, 3H), 7.35 (d, J=8.3 Hz, 2H), 7.51 (d, J 7.8H, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][Br:12]
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1CBr
Yield: 108.1 %

Procedure:
To a solution of 57.4 g (0.27 mole) of 2-bromo-6-nitro toluene in 800 ml of carbon tetrachloride was added 52.0 g (0.29 mole) of N-bromosuccinimide and 2.5 g of benzoyl peroxide. The mixture was heated to reflux for 64 hr., cooled and filtered. Removal of the solvent in vacuo afforded 86.1 g of a viscous oil. Purification was effected by washing through alumina (CCl4 /ether) and crystallization from ethyl alcohol; mp 61.5°-63°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8])([O-])=O.[H][H]>C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[C:7]([NH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: [H][H]
Reactant: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Nc1cccc(C(=O)Nc2ccc(C(=O)N3CCCc4ccccc43)cc2)c1
Yield: 79.9 %

Procedure:
Ethanol (50 ml) is added to 10% Pd--C (0.1 g) and thereto is added-1-[4-(3-nitrobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.73 g). The mixture is subjected to catalytic reduction at ordinary temperature under atmospheric pressure of hydrogen. After completion of the reduction, 10% Pd--C is removed by filtration and the filtrate is concentrated under reduced pressure. The residue is extracted with dichloromethane and the extract is dried over magnesium sulfate. The solvent is distilled off under reduced pressure and recrystallized from methanol to give 1-[4-(3-aminobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.54 g) as white powder, m.p. 205.5°-206.5° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CCOCC>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane product (1.0 g, 3.37 mmol) in anhydrous ether (30 mL) was added N-methylpiperizine (1.0 g, 10.1 mmol). The solution was stirred at RT for 14 hours and filtered through Celite™. The filtrate was evaporated under vacuum to give a crude product that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccnc1Cl
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a stirred solution of 2-chloronicotinic acid (10.0 g, 63.4 mmol) in anhydrous THF (150 mL) at 0° C. under N2 was added lithium aluminum hydride (63 mL of a 1.0M solution in THF, 63 mmol) over 10 minutes. The solution was allowed to warm to room temperature over 2 h. Small quantities of ice were carefully added to quench the reaction followed by water. The aqueous solution was extracted with ether. The combined organic extracts were washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to give the title compound of Step A as an orange solid (6.18 g). 1H NMR (CDCl3, 300 MHz) δ8.30 (dd, 1H), 7.90 (dd, 1H), 7.29 (dd, 1H), 4.80 (s,2H), 2.42 (br s,1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([Cl:12])[Cl:11].C(S([O-])(=O)=O)CCCCCCC.[Na+]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([CH2:9][SiH:10]([Cl:12])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Agent: CCCCCCCCS(=O)(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1
Yield: 46 %

Procedure:
Reaction between styrene and methyldichlorosilane with platinum catalyst in the presence of sodium 1-octanesulfonate. 624 mg Styrene and 732 mg methyldichlorosilane were introduced into a glass tube, and 40 mg of sodium 1-octanesulfonate were added with a microsyringe. 0.9 mg Of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) was added. The tube was sealed with Teflon tape and a rubber septum and then placed in a 100° C. oil bath where it was heated for 20 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 71% and a phenethylmethyldichlorosilane yield of 46%. The ratio between the phenethylmethyldichlorosilane and the (α-methylbenzyl)methyldichlorosilane was 18:1.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(OCC)C>[CH2:12]([O:19][C:20]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.9 %

Procedure:
To a solution of nipecotic acid 10 g, 63.6 mmol) in 1 N NaOH (2.5 g in 64 mL water, 63.6 mmol) at 0° C. was alternately added benzyloxycarbonyl chloride (10.9 mL, 76.5 mmol) in diethyl ether (50 mL) and 1 N NaOH (5 g in 128 mL water, 127.2 mmol) in five portions. The reaction mixture was stirred at 0° C. for 2 hours, and at ambient temperature for 24 hours. Then this was made acidic with 10% HCl and the solid formed was filtered and dried (vacuum oven, 45° C.) to obtain the title compound (18.9 g, 113%). MS (ESI) m/e 264 (M+H)+.
Reaction SMILES: [CH3:1][SH:2].[Na].[F:4][C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>C(O)C>[CH3:1][S:2][C:11]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]=1[C:5]([F:17])([F:16])[F:4]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS
Agent: [Na]
Solvent: CCO
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 17 h
Yield: 33.2 %

Procedure:
A mixture of 30 g of methyl mercaptan in 50 ml of ethanol was added at 10° C to a mixture of 12.5 g of sodium in 500 ml of ethanol and then 63 g of 3-trifluoromethyl-4-chloro-nitrobenzene were added thereto. The mixture stood at room temperature for 17 hours and was vacuum filtered. The recovered precipitate was washed with water and dried to obtain 22 g of 4-methylthio-3-trifluoromethyl-nitrobenzene melting at 158° C.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:14][OH:15])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:16][C:17]([CH3:19])=O.COC(OC)(C)C.S(=O)(=O)(O)O>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:16][C:17]1([CH3:19])[O:1][CH2:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:14][O:15]1
Reactant: CCOC(=O)C(CO)(CO)C(=O)OCC
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(C)(C)OC
Product: CCOC(=O)C1(C(=O)OCC)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 94 %

Procedure:
To a clear solution of diethyl bis(hydroxymethyl)malonate in 478 mL (6.52 mol) of acetone and 478 mL (8.45 mol) of acetone dimethylacetal was added 1.1 mL (42 mmol) of concentrated sulfuric acid and the reaction was stirred at room temperature overnight (19 hours). After 120 mL of saturated sodium carbonate was added, the mixture was stirred at room temperature for 15 minutes. The layers were separated and the semi-crystalline residue was washed with acetone (2×250 mL). The organics were evaporated. The residue was dispersed in 500 mL of ether and 250 mL of saturated Na2CO3, and stirred for 20 minutes. After the layers were separated, the organic layer was stirred with 250 mL of brine for 5 minutes and the layers separated. The organic layer was dried, evaporated, and placed under vacuum for 3 hours to produce a colorless oil, 527.5 g, in 94% yield.
Reaction SMILES: B.[I:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](O)=[O:11])[CH:6]=[CH:7][CH:8]=1>C1COCC1>[I:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(I)c1
Agent: B
Solvent: C1CCOC1
Product: OCCc1cccc(I)c1

Procedure:
2-(3-Iodophenyl)ethanol was prepared by borane reduction of 3-iodophenylacetic acid in THF in a similar manner as outlined in Example 17, and additionally purified by CC on SiO2 with EtOAc/hexane 2:3.
Reaction SMILES: C(N)C1C=CC=CC=1.C([C:12]([F:23])([F:22])[C:13]1[N:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=1)(O)=O.P(=O)(O)(O)O.[OH-].[Na+].C(OC(C)C)(=O)C.Cl>C1(C)C=CC=CC=1.O>[F:23][CH:12]([F:22])[C:13]1[N:14]=[CH:15][C:16]([C:19]([OH:21])=[O:20])=[N:17][CH:18]=1
Reactant: O=C(O)c1cnc(C(F)(F)C(=O)O)cn1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1cnc(C(F)F)cn1
Temperature: 110 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
To a mixture of benzyl amine salt of 5-[carboxy(difluoro)methyl]pyrazine-2-carboxylic acid (IV, 110 g, 0.245 mol) and water (460 mL) were added toluene (550 mL) and an aqueous sodium hydroxide solution (5 M, 127 mL), and the aqueous layer was separated. After addition of phosphoric acid (85%, 121 mL, 1.78 mol) to the obtained aqueous layer and stirring the mixture at 110° C. for 24 h, and the reaction was cooled to room temperature. An aqueous sodium hydroxide solution (48%, 140 mL) was added, and the resulting mixture was stirred at 110° C. for 22 h and then cooled to room temperature. After addition of isopropyl acetate (412 mL) and concentrated hydrochloric acid (210 mL), the mixture was passed through a filter and the filter was rinsed with isopropyl acetate (137 mL). After phase separation of the obtained mixture, the aqueous layer was re-extracted with isopropyl acetate (550 mL). The obtained two organic layers were combined and washed six times with water (165 mL each), and the six washings were combined and re-extracted with isopropyl acetate (550 mL). After combining the obtained two organic layers, concentration at 50° C. under reduced pressure, and cooling the residue (about 93 mL) to 20° C. followed by addition of n-heptane (155 mL) over 1 h, the mixture was cooled to −10° C. The precipitated solids were collected by filtration, washed with n-heptane (53 mL), and dried at 50° C. under reduced pressure to afford the title compound (V, 29.1 g, 66% yield) as yellow solids.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8](Cl)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)[N:9]=2)[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1sc2ncc(Cl)nc2c1N
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncc(-c3ccsc3)nc2c1N
Temperature: 95 °C
Yield: 88 %

Procedure:
A solution of the methyl 7-amino-2-chlorothieno[2,3-bjpyrazine-6carboxylate prepared as described in Example 10C (0.190 g), thiophene-3-boronic acid (0.100 g), Pd(dppf)Cl2 (0.032 g) and triethylamine (0.22 mL) in degassed DMF was heated to 95° C. for 4 h, cooled, quenched in water and extracted with 1:1Et2O/EtOAc (3×). The organics were washed 3× with water, brine, dried (Na2SO4), filtered and solvent evaporated to give 0.200 g (88%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.95 (3H, s), 6.23 (2H, br s), 7.50 (1H, dd), 7.79 (1H, dd), 8.05 (1H, dd), 9.00 (1H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27]CS([O-])(=O)=O)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1.Cl.[C:34]1([C:40]2([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.CO.ClCCl.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:26][CH2:27][N:43]3[CH2:42][CH2:41][C:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:46]([NH2:48])=[O:47])[CH2:45][CH2:44]3)[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=3)[CH2:8]2)[CH:2]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccnc3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccnc3)C2)cc(OC)c1OC
Reaction time: 70 h

Procedure:
Combine 2-[3-(pyridin-3-yl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.30 g, 0.65 mmol), 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.22 g, 0.9 mmol), and potassium carbonate (0.25 g, 1.8 mmol) in tetrahydrofuran (6 mL)/water (2 mL). Heat to reflux. After 70 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with ethyl acetate, 2% methanol/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane, 8% methanol/dichloromethane, and then and 10% methanol/dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:67][CH2:68][CH2:69][O:70][CH2:71][CH2:72][O:73][CH2:74][CH2:75][O:76][CH2:77][CH2:78][NH2:79]>O1CCCC1>[NH2:79][CH2:78][CH2:77][O:76][CH2:75][CH2:74][O:73][CH2:72][CH2:71][O:70][CH2:69][CH2:68][NH:67][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: NCCOCCOCCOCCN
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 200 mg, 324 μmol) and HATU (136 mg, 357 μmol) combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred for 30 min at room temperature. The reaction mixture was slowly added dropwise to a solution of 1,11-diamino-3,6,9-trioxaundecane (312 mg, 304 μL, 1.62 mmol) in dry tetrahydrofuran (1.5 mL) at 0° C. The reaction was done after stirring at room temperature for 20 min. It was filtered and injected into Gilson reverse-phase high-performance liquid chromatography for purification. The desired fractions was converted to free base and lyophilized to afford (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide as a white solid (169 mg, 66% yield). LCMS (ES+) m/z calcd. for C39H47Cl2F2N5O6 [(M+H)+]: 790. found: 790.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][C:13]1[C:18]2[NH:19][C:20](=[O:22])[O:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:15]2[CH:14]=[C:13]([CH3:12])[C:18]3[NH:19][C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)nc(Cl)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
10.0 g (47.5 mmol) 2,6-dichloropyridine-4-carboxylic acid chloride, 7.08 g (47.5 mmol) 4-methyl-3H-benzoxazol-2-one and 32.0 g (240 mmol) aluminium trichloride were heated to 120° C. for 1 h with stirring. The mixture was mixed with ice water and extracted several times with EtOAc. The solid precipitated from EtOAc was suction filtered and washed with EtOAc. The organic phase remaining was separated off, dried on sodium sulphate, filtered and evaporated down. The residue was combined with a little EtOAc, the precipitated solid was suction filtered and washed with a little EtOAc. For further purification the mixture was recrystallised from EtOAc.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C(=O)=O.CC(O)C.[Li]CCCC.C[O:24][B:25](OC)[O:26]C.Cl.[NH4+].[Cl-]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([B:25]([OH:26])[OH:24])[CH:7]=1
Reactant: COB(OC)OC
Reactant: COc1ccc(F)cc1Br
Agent: Cl
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COc1ccc(F)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
In a 200-mL flask, a solution of 2-bromo-4-fluoroanisole (Aldrich: 4.00 mL, 30.8 mmol) in THF (50 mL) was cooled to -78° C. (CO2 /IPA). To this solution n-BuLi (Aldrich: 2.5 M in hexanes; 12.4 mL, 31 mmol, 1.0 equivuiv) was added dropwise over a 30 min period. The reaction mixture was stirred at -78° C. for 60 min and treated with trimethylborate (Aldrich: 10.5 mL, 92.4 mmol, 3.0 equivuiv). The reaction mixture was allowed to slowly warm to rt, stirred overnight (12h), and cooled to 0° C. (ice/H2O). The solution was treated with 5% HCl until the pH reached 6. The reaction mixture was poured into sat'd NH4Cl (80 mL) and extracted with CH2Cl2 (3×100 mL). The extracts were washed with sat'd NH4Cl (1×80 mL), combined, dried (MgSO4), filtered through a pad of Celite™, and concentrated to afford 4.90 g (94%) of a white semi-solid. Data for 5-fluoro-20methozyphenylboronic acid: 1H NMR (400 MHz, acetone-d6): 7.47 (dd,J=8.8, 3.3, 1H); 7.17 (m, 1H); 7.05 (dd,J=9.0, 3.9, 1H); 3.93 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 1 g (4.69 mmol) of 4-oxo-azepane-1-carboxylic acid tert-butyl ester), in 2 mL of Methanol and 8 mL of THF, is added at 0° C. (ice bath) sodium tetrahydroborate (0.18 g, 4.69 mmol). The resulting mixture is stirred at 0° C. for 1 h. To the reaction mixture is added at 0° C. (ice bath), a solution of HCl (1N) (2 mL), then solvent is removed and the resulting slurry is diluted with water and extracted with EtOAc (250 mL). The organic layers are combined, dried (Na2SO4), filtered and concentrated to afford the title compound as a colorless oil (0.95 g, 94%). MS (m/e): 216 (M+1).