Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2cc(Cl)cc(Cl)c2)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 5.1 g of 3,5-dichlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 135°-137° C.). 1H NMR (CDCl3) δ2.78 (dd, 1H), 2.97 (dd, 1H), 3.63 (dd, 2H), 5.64 (dd, 1H), 7.31-7.40 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@:5]([CH3:10])([CH:7]=[N:8][OH:9])[CH2:4][O:3]1.[Cl:12]N1C(=O)CCC1=O>CN(C=O)C.O>[OH:9][N:8]=[C:7]([Cl:12])[C@:5]1([CH3:10])[CH2:4][O:3][C:2]([CH3:11])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)OC[C@@](C)(C=NO)O1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
(R)-2,2,4-Trimethyl-1,3-dioxolane-4-carbaldehyde oxime (4.8 g, 30 mmol) was dissolved in DMF (100 mL) and 1-chloropyrrolidine-2,5-dione (4.0 g, 30 mmol) was added. The reaction was stirred at ambient temperature overnight, then poured in water (600 mL) with of stirring. After 15 minutes the cloudy suspension was extracted with EtOAc and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated, to afford (S)-N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28 mmol, 94% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1.[C:26](O)(=[O:30])[CH:27]([CH3:29])[OH:28]>>[Cl:2][C:3]1[N:4]=[C:5]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:6]2[S:11][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:26](=[O:30])[C@@H:27]([OH:28])[CH3:29])[CH2:15][CH2:14]3)=[C:9]([CH3:19])[C:7]=2[N:8]=1
Reactant: CC(O)C(=O)O
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)[C@H](C)O)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate (777 mg) was subjected to General Procedure E to give the HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine. The HCl salt of 2-chloro-7-methyl-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (590 mg) was reacted with lactic acid via General Procedure B-2 to give (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=5[CH3:27])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Cc1ccccc1B(O)O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-phenylboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 3): tR=0.90 min; Mass spectrum (ESI+): m/z=471 [M+Na]+.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1O)CCCC3
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Ethyl 4-hydroxy-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate (Preparation 3, 150 g, 515 mmol) was added portionwise to phosphorus oxychloride (450 mL, 4.92 mol) and the resulting mixture stirred at 100° C. for 1 hour and then cooled to room temperature. The volatiles were removed in vacuo, and the residue was carefully poured into a vigorously stirred ice/water mixture. Ethyl acetate (500 mL) was added to the mixture. The mixture was adjusted to pH 8, by addition of 10M aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was further extracted with ethyl acetate (3×500 mL). The combined organic extracts were washed with brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting oil was poured into a crystallisation dish, where it solidified on standing to give the title compound, 140.69 g, in an 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, 3 H), 1.86-1.89 (m, 4 H), 2.59 (s, 3 H), 2.82-2.84 (m, 2 H), 3.08-3.11 (m, 2 H), 4.46 (q, 2 H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([C:20](=[O:26])[NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:22])[CH3:25]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To a solution of naphthalen-2-amine (2 g, 14.0 mmol) in dichloromethane (30 ml) was added triethylamine (4.24 g, 41.9 mmol, 3 eq). Then, ethyl 2-chloro-2-oxoacetate (1.92 g, 14.1 mmol, 1 eq) was added dropwise to the solution kept at 0-5° C. using an ice-bath. The resulting solution was allowed to warm to room temperature while stirring. The reaction was then quenched by the addition of water (50 ml), the product was extracted with dichloromethane (2×50 ml), and the organic layers were combined. The organic solution was washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, filtered, and then concentrated under vacuum to afford ethyl[(naphthalen-2-yl)carbamoyl]formate as a black solid (3 g, 88%). (ES, m/z) [M+H]+ 244; 1H NMR (300 MHz, CDCl3): δ 9.06 (broad s, 1H), 8.32 (d, J=1.8 Hz, 1H), 7.72-7.88 (m, 3H), 7.59 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.53 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C[Si](I)(C)C.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]#[N:28])[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3ccnc(C#N)c3)n2)CC1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(-c2nc(COC3CCNCC3)no2)ccn1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-[5-(2-cyanopyridin-4-yl)[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 42, 2.0 g, 5.2 mmol) in chloroform (100 ml) under argon, was added trimethylsilyl iodide (2.95 ml, 20.8 mmol) and the reaction mixture stirred for 1 h MeOH was added until a solution formed then sodium thiosulphate (6.6 g, 41.5 mmol) was added and the reaction mixture stirred vigorously for 10 min. The solids were removed by filtration and the filtrate adsorbed onto silica gel. Purification via column chromatography (DCM-MeOH, 9:1) afforded the title compound: RT=1.92 min; m/z (ES+)=286.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2/[C:13](=N/[S@](C(C)(C)C)=O)/[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:24]1CCCC1>>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C:13](=[O:24])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Reactant: C1CCOC1
Agent: Cl
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S,E)-N-((3aS,6aR)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (2.67 g, 8.38 mmol) from Example 14 Step A and 2.0 N aqueous HCl (18.86 mL, 37.7 mmol) were combined in tetrahydrofuran (25 mL). The reaction was stirred at room temperature for 2 hours and the tetrahydrofuran was removed in vacuo and the remaining aqueous portion was made slightly basic with aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3×200 mL of dichloromethane. The combined organic layers were separated, and the solvent was removed in vacuo. The crude material was purified on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 5-50% ethyl acetate/hexanes to give (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.16 (m, 5H), 3.61 (d, J=13.1, 1H), 3.48 (d, J=13.1, 1H), 3.02 (dd, J=1.8, 9.1, 1H), 2.96-2.82 (m, 1H), 2.71-2.56 (m, 2H), 2.43 (dt, J=8.2, 17.4, 3H), 2.34-2.21 (m, 1H), 2.12 (ddd, J=8.3, 13.0, 16.9, 1H), 1.79 (dddd, J=4.2, 6.4, 9.2, 13.2, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([F:20])[CH:27]=[C:26]([F:28])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-difluoroaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.94 (d, 1H, J=3.3 Hz), 7.20-7.11 (m, 3H), 7.02 (s, 1H), 6.92-6.90 (m, 2H), 6.65 (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz), 4.31 (s, 4H); 19F NMR (282 MHz, CDCl3): −31142, −47002; LCMS: purity: 97%; MS (m/e): 375 (MH+).
Reaction SMILES: O.[OH-].[Na+].O.Cl.[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].Cl[C:14](OC1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[O:15]=[C:14]1[NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][S:9]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1N[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A aqueous solution comprising 0.88 liter of water and 184.0 g of sodium hydroxide was dissolved 175.6 g of L-cysteine monohydrochloride monohydrate under ice-cooling, 0.35 liter of a toluene solution containing 313.2 g of phenyl chloroformate was added to the above solution within a range not exceeding 30° C. After stirring the mixture at room temperature for 2 hours, it was allowed to stand and the liquids were separated. The aqueous layer was washed with 0.35 liter of toluene, the layers were separated, and the aqueous layer was concentrated to give 139.84 g of (4R)-2-oxothiazolidin-4-carboxylic acid as colorless crystal.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=3[O:25][CH3:26])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[C:32]([F:34])[CH:33]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[O:12][C:11]([NH:13][C:14]4[CH:19]=[C:18]([S:20]([CH2:23][CH3:24])(=[O:21])=[O:22])[CH:17]=[CH:16][C:15]=4[O:25][CH3:26])=[N:10][CH:9]=3)[CH:3]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(Br)c3)o2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(OC)c(Nc2ncc(-c3cccc(-c4cc(F)cc(F)c4)c3)o2)c1
Temperature: 100 °C
Yield: 63 %

Procedure:
In a pyrex sealed tube, a mixture of the title compound of Example 100 (123 mg, 0.28 mmol), 3,5-difluoro(tributylstannyl)benzene (400 mg, 1 mmol), tetrabutylammonium chloride (170 mg, 0.61 mmol), and tetrakistriphenylphosphine palladium(0) (20 mg, 0.017 mmol) was suspended in dry acetonitrile (10 mL) and stirred at 100° C. After the reaction was determine to be complete by TLC analysis, the reaction was cooled and diluted with ethyl acetate (50 mL), quenched with 1M aqueous potassium fluoride solution (20 mL), and stirred for 3 h. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (1:1) to afford the title compound (83 mg, 63%) as a solid white powder. 1H NMR (400 MHz, d6-DMSO): δ 9.72 (s, 1H), 8.74 (d, J=2.2, 1H), 7.91 (s, 1H), 7.60–7.64 (m, 3H), 7.42–7.53 (m, 4H), 7.23 (d, J=8.6, 1H), 3.94 (s, 3H), 3.16 (q, J=7.3, 2H), 1.07 (t, J=7.3, 3H). MS (ES+, m/z)=471 (m+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH2:25][CH2:26][CH3:27]>ClCCl>[CH2:24]([O:28][C:29]([N:13]1[CH2:14][CH2:15][CH:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])[CH2:12]1)=[O:30])[CH2:25][CH2:26][CH3:27]
Reactant: O=C(NC1CCNC1)OCc1ccccc1
Reactant: CCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 3.20 g pyrrolidin-3-yl-carbamic acid benzyl ester hydrotrifluoracetate in 50 ml dichloromethane were added dropwise 3.7 ml triethylamine and 1.3 ml butylchloro-formate at 0° C. After stirring for 12 h the reaction mixture was diluted with dichloromethane, washed with 0.1 M HCl, saturated NaHCO3 and brine. The crude product thus obtained was purified by flash chromatography on silica using ethyl acetate/heptane 1:2 as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](CCCC)(CCCC)CCCC)[S:10][C:3]=12.Br[C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1.C1(C)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:25]3[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=3)[S:10][C:3]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nccc(Cl)c2s1
Reactant: Cn1ccnc1Br
Solvent: Cc1ccccc1
Product: Cn1ccnc1-c1cc2nccc(Cl)c2s1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of the tin derivative 6 (24.79 g, 54.05 mmol) and 2-bromo-1-methyl-1H-imidazole (10.4 g, 64.86 mmol) [McCallum, P. W.; Weavers, R. T.: Grimmet, M. R.; Blackman, A. G.; Aust. J. Chem.; 52; 3; 1999; 159-166.1 in toluene (180 mL) Pd[PPh3]4 (5 g, 4.32 mmol) was added and the mixture was refluxed under nitrogen for 2 days, cooled to room temperature. A precipitate was formed which was collected by filtration, washed with Et2O and dried, to afford the title compound 7 as a grey solid (12.72 g, 94% yield). MS (m/z): 250.0 (M+H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].CN1CCCC1=[O:19]>O>[OH:19][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: CN1CCCC1=O
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: O
Product: COc1ccc(C(=O)CO)cc1

Procedure:
It is used in the synthesis of MOPMN, above, and was synthesized from 2-bromo-4'-methoxyacetophenone (Aldrich). The 2-bromo-4'-methoxyacetophenone was refluxed in 20% water and N-methyl-2-pyrrolidinone for 10 hours at 105° C. The product was extracted with ethylether, dried over MgSO4, the ether evaporated and the dry solid recrystallized before use. Melting point 98.5°-100.5° C. and the NMR corresponds to the product.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][C:23]=3[O:24][CH3:25])[NH:20][CH:19]=[C:18]4[C:26](=[O:32])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C[Si]([N-:39][Si](C)(C)C)(C)C.[Li+]>CN1CCCC1=O>[NH2:39][N:20]1[C:21]2[C:17](=[CH:16][C:15]([C:13]([N:10]3[CH2:11][CH2:12][CH:7]([CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)=[O:14])=[C:23]([O:24][CH3:25])[CH:22]=2)[C:18]([C:26](=[O:32])[C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:19]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1cc2[nH]cc(C(=O)C(=O)N(C)C)c2cc1C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(cc1C(=O)N1CCC(Cc3ccc(F)cc3)CC1)c(C(=O)C(=O)N(C)C)cn2N
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To a solution of 2-{5-[4-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-6-methoxy-1H-indol-3-yl}-N,N-dimethyl-2-oxo-acetamide (620 mg, 1.33 mmol) in 1-methyl-2-pyrrolidinone (20 mL) was added lithium bis(trimethylsilyl)amide (2.1 mL, 2.1 mmol, 1.0 M in THF) at −10° C., followed by o-(diphenylphosphinyl)hydroxylamine (350 mg, 1.5 mmol). The reaction mixture was allowed to warm to RT and continually stirred for 6 h, then quenched with water (50 mL). The resulting mixture was extracted with EtOAc, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by radial chromatography eluting with 2% MeOH in CH2Cl2 to give 300 mg (47%) of the desired product as a white solid. M+H+(481).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24]([OH:26])=O)/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([NH:45][CH2:46][C@@H:47]2[NH:51][CH2:50][C@H:49]([OH:52])[CH2:48]2)[CH2:44][CH2:43]1>CN(C=O)C>[CH:42]1([NH:45][CH2:46][C@H:47]2[CH2:48][C@@H:49]([OH:52])[CH2:50][N:51]2[C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:26])[CH2:44][CH2:43]1
Reactant: O[C@H]1CN[C@@H](CNC2CC2)C1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)N2C[C@H](O)C[C@@H]2CNC2CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.28 mmol), EDC (64 mg, 1.2 eq.), HOBt (45 mg, 1.2 eq.) in DMF (3 mL) was added TEA (0.098 mL) and (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol. The mixture was stirred at rt for overnight. After the usual work up, 65 mg of the titled compound was obtained as a yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:7]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[OH-].[Na+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(OCC)(=O)C>[C:24]1([CH2:30][C:31]([NH:2][CH:3]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[C:4]([OH:6])=[O:5])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC(C(=O)O)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
An aqueous solution (188 mL) of 2-amino-3,3-bis(4-fluorophenyl)propanoic acid hydrochloride (21.50 g, 68.9 mmol) was adjusted to pH 12.2 with 1M aqueous sodium hydroxide solution (154.2 g). Phenylacetyl chloride (10.8 mL, 81.7 mmol) was added dropwise at 0-10° C. while adjusting the mixture to pH 11-12 with 1M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 hrs. Ethyl acetate (400 mL) was added to the reaction mixture, and the mixture was adjusted to pH 1.1 with concentrated hydrochloric acid and partitioned. The obtained organic layer was warmed to 40° C. and hexane (525 mL) was added. The mixture was cooled in an ice bath to allow solid precipitation. The solid was collected by filtration and dried to give the title compound (21.75 g).
Reaction SMILES: C([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:30])C1C=CC=CC=1.O1CCCC1>C(O)C>[CH2:35]([C:33]1[CH:32]=[CH:31][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:20])=[O:19])=[CH:14][C:13]=2[F:30])=[C:9]([OH:8])[CH:34]=1)[CH3:36]
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(Oc2ccc(S(=O)(=O)NCCc3ccccn3)cc2F)c(O)c1
Yield: 56 %

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for 4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzene sulfonamide (150 mg; 0.30 mmol) and tetrahydrofurane for ethanol (3 mL), the title compound (70 mg; 62%) was obtained as a clear oil, after purification via preparative TLC (dichloromethane/ethyl acetate).
Reaction SMILES: [N:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3].O.[BH4-].[Na+]>C1COCC1>[N:1]([CH:4]1[CH:13]([OH:14])[C:12]2[C:7](=[CH:8][C:9]([C:15]#[N:16])=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)OCC(N=[N+]=[N-])C2O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.3 %

Procedure:
Racemic 3-azido-4-oxochroman-7-carbonitrile Int-2-B (2.30 g, 10.8 mmol) was dissolved in THF (103 mL) and water (5.42 mL) at 0° C. To this solution was added sodium borohydride (0.53 g, 14.1 mmol). The reaction mixture was stirred at 0° C. for 45 mins. Next, the reaction was quenched by addition of 1N HCl. The resulting solution was extracted with EtOAc and washed with water and brine. The organic layers were combined, dried (MgSO4) and concentrated to give racemic (3R*,4S*)-3-azido-4-hydroxychroman-7-carbonitrile Int-2-C (2.21 g, 10.2 mmol, 94.3% yield): LCMS=217.06 [M+H]+.