Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:35]([O:37][C:38](=[O:42])[CH2:39][CH2:40][NH2:41])[CH3:36].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH:6]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH:41][CH2:40][CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:42])=[O:30])=[CH:27][N:26]=2)[C:7]2[CH:12]=[C:11]([CH3:13])[C:10]([N:14]3[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[N:15]3)=[C:9]([CH3:23])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(Nc2ccc(C(=O)O)cn2)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C)c(-n3cc(C(F)(F)F)cn3)c(C)c2)C2CCCC2)nc1
Reaction time: 70 h

Procedure:
To a mixture of (+/−)-6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinic acid (731 mg, 1.59 mmol), β-alanine ethyl ester hydrochloride (516 mg, 3.19 mmol), and 1-hydroxy-7-azabenzotriazole (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was diluted with dichloromethane (50 mL) and washed with water (3×50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried (Na2SO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate/heptane) followed by chiral SFC (Cellulose-2 column, 21 mm×250 mm, 35% methanol/carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 1 (SFC retention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)amino)nicotinamido)propanoate, Isomer 2 (SFC retention time 3.43 min). 1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.81-7.72 (m, 2H), 7.09 (s, 2H), 6.84 (t, J=5.7 Hz, 1H), 6.41-6.27 (m, 1H), 6.26 (d, J=9.0 Hz, 1H), 4.33 (t, J=7.6 Hz, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.65 (q, J=6.0 Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 2.33-2.19 (m, 1H), 1.98 (s, 6H), 1.96-1.85 (m, 1H), 1.74-1.37 (m, 6H), 1.34-1.21 (m, 4H). MS (M+1): 558.5.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[C:18]2[S:17](=[O:20])(=[O:19])[N:16]=[C:15]([C:21]3[C:22](=[O:37])[N:23]([NH:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)[C:24]4[C:29]([C:30]=3[OH:31])=[CH:28][CH:27]=[CH:26][CH:25]=4)[NH:14][C:13]=2[S:12][CH:11]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[CH:34]1([CH2:33][NH:32][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]([OH:31])=[C:21]([C:15]3[NH:14][C:13]4[S:12][CH:11]=[C:10]([CH2:9][NH:8][S:39]([CH3:38])(=[O:41])=[O:40])[C:18]=4[S:17](=[O:19])(=[O:20])[N:16]=3)[C:22]2=[O:37])[CH2:35][CH2:36]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
To the suspension of the triethylamine salt of 3-[7-(aminomethyl)-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-1-[(cyclopropylmethyl)amino]-4-hydroxyquinolin-2(1H)-one (85.26 mg, 0.16 mmol) in N,N-dimethylformamide (1.6 mL) was added triethylamine (48 □L, 0.34 mmol) and then methanesulfonyl chloride (13.3 □L, 0.17 mmol) at room temperature. The solution was stirred at room temperature for 20 minutes and concentrated in vacuo. The residue purified by reverse phase chromatography, eluting with 20% to 95% acetonitrile/0.1% triflouroacetic acid in water to give N-[(3-{1-[(cyclopropylmethyl)amino]-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl}-1,1-dioxido-4H-thieno[2,3-e][1,2,4]thiadiazin-7-yl)methyl]methanesulfonamide (compound II) (39.86 mg, 49%). MS (ESI+) m/z 524 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ 0.15 (m, 2H) 0.42 (m, 2H) 1.01 (m, 1H) 2.84 (d, J=7.35 Hz, 2H) 2.99 (s, 3H) 4.29 (d, J=6.25 Hz, 2H) 6.37 (br s, 1H) 7.41 (m, 2H) 7.75 (t, J=6.25 Hz, 1H) 7.87 (m, 1H) 8.08 (d, J=8.09 Hz, 1H) 8.16 (m, 1H) 14.46 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[OH:10])=[CH:4][CH:3]=1.[Bi]=O>C(O)(=O)C>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:12][CH:13]=1
Reactant: CSc1ccc(C(O)C(=O)c2ccc(F)cc2)cc1
Agent: O=[Bi]
Solvent: CC(=O)O
Product: CSc1ccc(C(=O)C(=O)c2ccc(F)cc2)cc1
Temperature: 80 °C

Procedure:
A mixture of ketone from step 2 (1.25 g, 4.5 mmol) and bismuth oxide (Bi2O3) (2.7 g, 1.2 equiv.) in acetic acid (20 ml) was warmed to 80° C. for 30 minutes. After cooling, the mixture was filtered through Celite® filter agent and the filtrate was concentrated. The residue was dissolved in hot methanol and filtered. The solvent was concentrated under a nitrogen stream, placed in the refrigerator and the precipitate formed was filtered to give 1 g (83%) of titled dione: m.p. 96°-97° C. Anal. Calc'd. for C15H11FO2S (M.W. 274.31): C, 65.68; H, 4.04; S, 11.69. Found: C, 65.42; H, 3.85; S, 1.42.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[CH2:8][C@@H:7]1[CH2:6][O:5][C:4]2=[O:9].[H-].[Na+].[CH:12]1[CH:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>C1COCC1>[CH2:18]([O:1][CH2:2][C@@:3]12[CH2:8][C@@H:7]1[CH2:6][O:5][C:4]2=[O:9])[C:15]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC[C@H]2C[C@@]12CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC[C@H]2C[C@@]12COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (1R,5S)-1-(hydroxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one (3a, 100 mmol, prepared according to Moon, H. R., et al. Nucleosides, Nucleotides and Nucleic Acids, 2007, 26, 975-978) in THF (200 mL) at 0° C. was added NaH (60% in mineral oil, 4.80 g, 120 mmol). After 10 min, BnBr (120 mmol) was added. After stirring at room temperature for 12 h, the reaction was cooled to 0° C., and to the reaction was added saturate aqueous NH4Cl (50 mL) and water (50 mL). The mixture was extracted with ether (300 mL). The organic layer was washed with water (100 mL), brine (50 mL), dried over MgSO4, and concentrated. The residue was purified by column (0-20 ethyl acetate in hanexane) to give a colorless liquid (3b). LCMS (ESI) m/z=219 (M+1).
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]#[N:16].O.[NH2:18][NH2:19]>O1CCOCC1>[C:15]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[C:2]=1[NH:18][NH2:19])#[N:16]
Reactant: NN
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1Br
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1NN
Yield: 39.2 %

Procedure:
6.4 g (0.02 mol) of 5-bromo-4-cyano-1-(2,4-dichlorophenyl)-pyrazole and 15 g (0.2 mol) of hydrazine hydrate in 80 ml of dioxane are stirred at the reflux temperature for 20 hours, the mixture is then concentrated under reduced pressure and the residue is stirred with water, filtered off with suction and recrystallized twice from ethanol. 2.1 g (40% of theory) of 4-cyano-5-hydrazino-1-(2,4-dichlorophenyl)-pyrazole of melting point 199° C.-204° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)(=O)C.[H][H]>[Ni].C(O)C.O1CCCC1>[CH2:11]([NH:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC=O
Reactant: NCc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCCNCc1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 13 h
Yield: 29.1 %

Procedure:
71.6 g (0.50 mol) of 2,4-difluorobenzylamine, 100.2 g (1.0 mol) of caproaldehyde, 1.0 g of acetic acid, 10 g of Raney nickel in ethanol and 500 ml of tetrahydrofuran are introduced into a 1 l autoclave. This mixture is heated to 100° C. and hydrogenated with stirring and under a pressure of 100 bar. After 13 hours, the take-up of hydrogen is 142% of theory. The black suspension is filtered, and the filtrate is evaporated on a rotary evaporator and subsequently distilled at 77° C. and 2 mbar. 33.1 g of a colourless liquid are obtained.
Reaction SMILES: [CH:1]([I:4])(I)I.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH:15]=O)=[CH:8][CH:7]=1>C1COCC1.[Cr](Cl)(Cl)=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:19])[C:14]([CH3:17])([CH3:15])/[CH:18]=[CH:1]/[I:4])=[CH:10][CH:11]=1
Reactant: CC(C)(C=O)C(=O)Nc1ccc(Cl)cc1
Reactant: IC(I)I
Agent: O=[Cr](Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(/C=C/I)C(=O)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.5 %

Procedure:
To a stirred suspension of chromous chloride (3.3 g) in 75 mL of dry THF was added a solution of iodoform (3.5 g) and N-(4-chlorophenyl)-2,2-dimethyl-3-oxopropanamide (1 g) in 25 mL of THF, dropwise over 10 minutes. The solution was allowed to stir an additional 1.5 hour, then poured into 100 g of ice water and extracted into ether. The organic phase was dried, filtered and evaporated, and the residue was filtered through a small silica gel column, eluting with ether, to remove chromium residues. The title product (0.55 g) was isolated as a solid, m.p. 145°-146° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.[CH2:31]([C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([OH:52])=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])[CH:44]=2)[N:37]=1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:31]([C:33]1[S:34][CH:35]=[C:36](/[CH:38]=[CH:39]/[C:40]2[C:41]([O:52][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:42][N:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])[CH:44]=2)[N:37]=1)[CH3:32]
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3C)nc2O)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5C)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 19 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (552 mg), 4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-(2-methylphenyl)-1H-pyrazol-3-ol (400 mg), anhydrous potassium carbonate (177 mg) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:4-1:3-1:2, v/v). The obtained eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ethyl acetate-hexane to give ethyl [4-(4-{[4-({[4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-(2-methylphenyl)-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-5-methyl-1,3-oxazol-2-yl)phenyl]acetate as pale-yellow amorphous form (173 mg, yield 19%).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:2]3[C:1](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=3[NH:19][C:20]3=[CH:24][CH:23]=[N:22][N:21]23)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=C1CCCC(=O)C1
Reactant: Nc1cc[nH]n1
Product: O=C1CCCC2=C1C(c1ccc(F)c(Cl)c1)n1nccc1N2

Procedure:
1,3-Cyclohexanedione, 3-chloro-4-fluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[C:16](=[O:18])=[O:17]>C1COCC1>[Cl:8][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[C:16]([OH:18])=[O:17]
Reactant: Cc1cc(F)c(Br)cc1Cl
Reactant: O=C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(F)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 1-bromo-5-chloro-2-fluoro-4-methylbenzene (11.3 g, 50 mmol) in dry THF (100 mL) was added isopropylmagnesium chloride (30 mL, 2 M) dropwise. After stirring at room temperature for 30 min, dry CO2 was added and the mixture was stirred at room temperature for additional 30 min. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (50 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to give the desired product (4.7 g, 49%). LCMS (ESI) m/z: 187.0 [M−H]−.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:12]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[CH:10]=[N:9][CH:8]=1.O.CN([CH:23]=[O:24])C>>[Cl:6][C:7]1[C:8]([CH:23]=[O:24])=[N:9][CH:10]=[C:11]([N:13]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH3:14])[N:12]=1
Reactant: CN(CC1CC1)c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(CC1CC1)c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Phosphoryl chloride (0.43 mL) was added dropwise to DMF (1 mL) at 0° C. The mixture was stirred for 15 min, and a solution of 6-chloro-N-(cyclopropylmethyl)-N-methylpyrazin-2-amine (0.46 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 50° C. for 16 hr, water (5 ml) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (0.37 g, 71%) as a pale-yellow oil.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>CO>[Cl:11][C:7]1[CH:6]=[C:5]([C@@:3]2([OH:4])[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][C@@H:2]2[CH3:12])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(N)CO
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Solvent: CO
Product: C[C@H]1NC(C)(C)CO[C@]1(O)c1cccc(Cl)c1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
To a solution of 2-bromo-3′-chloropropiophenone (19.3g, 0.08 mol) in MeOH (100 mL) was added dropwise a solution of 2-amino-2-methyl-1-propanol (27.8 g, 0.31 mol) in methanol (200 mL) at ambient temperature. The mixture was stirred for 18 h and concentrated in vacuo. The residue was partitioned between water and diethyl ether. The combined organic phase was extracted with 10% aqueous hydrogen chloride. The combined aqueous acid extracts were chilled in an ice bath and made basic with 40% aqueous sodium hydroxide. The mixture was extracted with diethyl ether, the combined diethyl ether extracts were washed with water and saturated sodium chloride solution, dried (K2CO3) and concentrated in vacuo to give 15.0 g (75%) of (+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH2:9][CH3:10])[N:3]=1.[N:11]1([S:17]([C:20]2[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35](Cl)(=[O:37])=[O:36]>>[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:29]=1[S:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:23]2[CH:22]=[CH:21][C:20]([S:17]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)(=[O:19])=[O:18])=[CH:25][CH:24]=2)=[C:4]([CH2:9][CH3:10])[N:3]=1)(=[O:37])=[O:36]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Reactant: CCc1nc(N)ccc1Br
Product: CCc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-ethylpyridine and 4-(N -morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.00 (1 H, d, J 10 Hz, A-ring CH ortho to SO2NH), 7.50 & 6.98 (2×2 H, 2×d, C-ring CH's), 7.45 (1 H, d, J 10 Hz, A-ring CH ortho to Cl), 7.35 (1 H, s, A ring CH ortho to 2×Cl), 7.26 & 6.74 (2×1 H, 2×d, 2×J 10 Hz, pyridyl CH's), 3.63-3.56 (4H, m, CH2CH2), 2.88-2.79 (4H, m, CH2NCH2), 2.72 (3H, q, J 8 Hz, CH2CH3), 1.09 (3 H, t, J 8 Hz, CH2CH3). Hplc (Luna 2, Gradient 5): rt=6.19 minutes. LC/MS rt=6.86 minutes, 588/590 (MH+).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1CO.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.CN(C)[CH:21]=[O:22]>>[Br:18][C:15]1[CH:14]=[N:13][C:12]([O:22][CH2:21][C:7]2[CH:8]=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: OCc1ccccn1
Reactant: Brc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Product: Brc1ccc(OCc2cccnc2)nc1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Sodium hydride (144 mg, 3.6 mmol) was added to a solution of 2-pyridine-methanol (361 mg, 3.3 mmol) in dimethylformamide (5 ml) and stirred for 20 minutes. 2,5-Dibromopyridine (711 mg, 3.0 mmol) was added, the reaction was heated to 100° C. for 10 hours, before the reaction was cooled and the solvents removed in vacuo. 2.0 N aqueous sodium hydroxide solution (5 ml) was added, the aqueous layer was extracted with ethyl acetate which was washed with and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% ethyl acetate in isohexane, yielded 3-bromo-6-(3-pyridylmethoxy)pyridine (366 mg, 46% yield) as an off-white solid:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[C:4]([O:19][C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[C:25]3[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:31])[CH:3]=1.[NH2:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([N:53]2[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]2)(=[O:52])=[O:51])=[CH:46][CH:45]=1>>[F:40][C:39]([F:42])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:30]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[CH:27]=[CH:28][CH:29]=[C:20]3[O:19][C:4]2[CH:3]=[C:2]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([N:53]4[CH2:58][CH2:57][N:56]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:55][CH2:54]4)(=[O:51])=[O:52])=[CH:46][CH:45]=3)[N:7]=[C:6]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:18])[CH3:16])[CH:9]=[CH:10][C:5]=23)=[O:31])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3cccc4c(C(=O)Nc5cccc(C(F)(F)F)c5)cccc34)cc(Cl)nc21
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Nc3cc(Oc4cccc5c(C(=O)Nc6cccc(C(F)(F)F)c6)cccc45)c4ccn(COCC[Si](C)(C)C)c4n3)cc2)CC1
Yield: 70.5 %

Procedure:
tert-butyl 4-(4-(4-(5-(3-(trifluoromethyl)phenylcarbamoyl)naphthalen-1-yloxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)phenylsulfonyl)piperazine-1-carboxylate (42 mg, 70% yield) was prepared as described for Example 5-B starting from 5-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)-N-(3-(trifluoromethyl)phenyl)-1-naphthamide (40 mg, 0.065 mmol) and tert-butyl 4-(4-aminophenylsulfonyl)piperazine-1-carboxylate (22 mg, 0.065 mmol). MS m/z: 917 [M+1].
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(O)C(N)(CO)CO>ClCCCl>[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:9]3[CH2:13][CH2:12][C@@H:11]([N:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[CH3:19])[CH2:10]3)=[CH:5][CH:6]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of 4-fluoro-benzenesulfonyl chloride (53 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 6.9 mg of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:36])[C@H:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([F:35])[CH:28]=1)[CH3:25].COC(=O)COC1C=CC(CN)=C(F)C=1>>[CH3:21][O:22][C:23](=[O:36])[C@H:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:19][CH:18]=[C:17]([F:20])[CH:16]=2)=[O:15])=[C:29]([F:35])[CH:28]=1)[CH3:25]
Reactant: COC(=O)[C@@H](C)Oc1ccc(CN)c(F)c1
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Agent: COC(=O)COc1ccc(CN)c(F)c1
Product: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1

Procedure:
The compound of Formula (5.0.32) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid methyl ester for the corresponding 2-(benzo-[[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:10]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10]
Reactant: COP(OC)OC
Reactant: O=C(Cl)Oc1ccc(Cl)c(Cl)c1
Product: COP(=O)(OC)C(=O)Oc1ccc(Cl)c(Cl)c1

Procedure:
From 10.3 g (85 mmole) of trimethylphosphite and 13.5 g (60 mmole) of 3,4-dichlorophenyl chloroformate (100°, 2 hours). Yield 11.4 g (64%) B.p.0.04 154° C. nD20 1.5271. Solidifies to colourless crystals m.p. 58°-9° C. Analysis for C9H9Cl2O5P. Found (calculated): C 36.06 (36.14), H 3.31 (3.03), Cl 23.58 (23.71), P 10.50 (10.36). NMR (CDCl3)δ: 3.93 and 4.07 (CH3O), 7.0-7.6 (C6H3) IR (KBr)cm-1 : 1740 (CO), 1205, 1200, 1105, 1055, 1020.