Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[C:19]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
10 g (56.4 mmol) of (4S)-4-benzyl-2-oxazolidinone is dissolved under argon atmosphere in 100 ml of abs. THF and is mixed dropwise at -78° C. with 37 ml (59.3 mmol, 1.6M in hexane, 1.05 eq) of n-butyllithium. After 10 min., 4.1 ml (4.5 g, 57.5 mmol, 1.02 eq) of acetyl chloride is instilled. The solution is stirred for 15 more min. under cooling and then 3 hours at room temperature. For working up it is mixed with 50 ml of saturated ammonium chloride solution, the organic solvents are distilled off in a vacuum and the remaining residue is extracted several times with ethyl acetate. After drying on sodium sulfate and concentration by evaporation in a vacuum, the remaining solid is recrystallized in ethyl acetate/hexane. 10.3 g (83%) of colorless needles with melting point of 106° C. is formed.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([F:27])([O:6][C:7]([F:26])([F:25])[C:8]([C:21]([F:24])([F:23])[F:22])([F:20])[O:9][C:10]([F:19])([F:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:4][OH:5].Cl[CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH2:37])=[CH:34][CH:33]=1>>[F:1][C:2]([F:28])([F:29])[C:3]([F:27])([O:6][C:7]([F:25])([F:26])[C:8]([C:21]([F:24])([F:23])[F:22])([F:20])[O:9][C:10]([F:18])([F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:4][O:5][CH2:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH2:37])=[CH:34][CH:33]=1
Reactant: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reactant: C=Cc1ccc(CCl)cc1
Product: C=Cc1ccc(COCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)cc1
Yield: 70.2 %

Procedure:
As in Example 1, 96.4 grams (0.2 mol) of 2,5-bis-trifluoromethyl-2,4,4,5,7,7,8,8,9,9,9-undecafluoro-3,6-dioxanonanol was reacted with 30.6 grams (0.2 mol) of p-chloromethylstyrene, yielding as a fraction at 96°-97° C. and 1.4×10-4 mmHg 84 grams (yield 70%) of p-(4,7-bistrifluoromethyl-4,6,6,7,9,9,10,10,11,11,11-undecafluoro-2,5,8-trioxaundecyl)styrene. ##STR13##
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[C:21]([O:30][CH3:31])(=[O:29])/[CH:22]=[CH:23]/[CH2:24][C:25]([O:27][CH3:28])=[O:26].C1CCN2C(=NCCC2)CC1>CC#N>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:22][C:21]([O:30][CH3:31])=[O:29])[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: COC(=O)/C=C/CC(=O)OC
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CC(CC(=O)OC)n1cc(-c2nc(-c3cnn(C)c3)cc3nccn23)cn1
Temperature: 55 °C
Yield: 77.8 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K; 0.165 g, 0.622 mmol) was suspended in CH3CN (5 mL) and (E)-dimethyl pent-2-enedioate (0.295 g, 1.87 mmol) was added followed by DBU (0.0947 g, 0.622 mmol). The reaction was warmed to 55° C. and heated for 9 hours. The reaction was then cooled and concentrated. The residue was purified on silica gel (1-4% methanol in DCM) to afford dimethyl 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedioate (205 mg, 78% yield). MS (apci) m/z=424.2 (M+H).
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20]>C1COCC1.FC(F)(F)C(O)=O>[CH2:19]([O:21][CH:22]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:23])[CH3:20]
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Reactant: C=COCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC12CCCCCCCCCC1C(=O)CC(C)C2
Yield: 81.9 %

Procedure:
A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) ethyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 2 days. After a short column filtration (SiO2) using diethyl ether as eluent and evaporation of the solvent 2.6 g of the crude product (18) was obtained. Flash chromatography, using SiO2 and cyclohexanelEtOAc=95:5 as eluent, afforded 2.10 g (82%) of (18) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: CC(C)([O-])C.[Na+].[N:7]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]2[CH2:12][NH:13][CH2:14][CH:10]2[CH2:9][CH2:8]1.I[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:32]=1[N:31]=[CH:30][C:29]([S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])=[CH:28]2>O1CCOCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:36]1([S:33]([C:29]2[CH:30]=[N:31][C:32]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[N:13]2[CH2:14][CH:10]3[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:11]3[CH2:12]2)(=[O:35])=[O:34])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNCC21
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(I)cccc2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2CN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)CC21
Temperature: 40 °C
Yield: 37.6 %

Procedure:
A solution of sodium t-butoxide (70 mg, 0.71 mmol) and tert-butyl hexahydropyrrolo-[2,3-c]pyrrole-1(2H)-carboxylate (537 mg, 2.53 mmol) in dioxane (3 mL) was stirred under nitrogen. To this was added 1,1′-bis(diphenylphosphino)ferrocene (25 mg, 0.05 mmol), Pd2(DBA)3 (12 mg, 0.02 mmol) and 8-iodo-3-(phenylsulfonyl)quinoline (200 mg, 0.51 mmol), followed by the addition of a further 2 mL of dioxane. The mixture was then heated at 40° C. for 12 h before partitioning between CH2Cl2 and water. The mixture was filtered through Celite and the organic phase was separated. The water phase was extracted twice with CH2Cl2 and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo to provide the crude material, which was purified by flash chromatography to give the title compound (92 mg, 38%) as a light yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[O:10][CH2:11][C:12]=2[CH:13]=[CH:14][C:15](O)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:33][S:34][C:35]1[C:40]([NH2:41])=[C:39]([S:42][CH3:43])[CH:38]=[C:37]([CH3:44])[N:36]=1>C(Cl)Cl.O.N1C=CC=CC=1>[CH3:33][S:34][C:35]1[C:40]([NH:41][C:15](=[O:16])[CH:14]=[CH:13][C:12]2[CH2:11][O:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:39]([S:42][CH3:43])[CH:38]=[C:37]([CH3:44])[N:36]=1
Reactant: O=C(O)C=CC1=C(c2ccccc2)c2ccccc2OC1
Reactant: CSc1cc(C)nc(SC)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CSc1cc(C)nc(SC)c1NC(=O)C=CC1=C(c2ccccc2)c2ccccc2OC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
1 g (3.59 mmol) of 3-(4-phenyl-2H-3-benzo[b]-pyranyl)prop-2-enoic acid in solution in 30 ml of methylene chloride is placed in a 250-ml reactor protected from moisture, and a drop of dimethyl-formamide is added thereto. 0.39 ml (3.76 mmol) of oxalyl chloride is poured dropwise into this solution kept at room temperature. The reaction medium is then heated under reflux for 1 hour. After evaporation of the solvent, the reaction medium is taken up in 20 ml of methylene chloride. This solution is then poured into a mixture kept between 0 and 5° C. consisting of 0.75 g (3.76 mmol) of 2,4-dimethylthio-6-methyl-3-pyridylamine, 2.2 ml of pyridine and 30 ml of methylene chloride. The resulting reaction medium is stirred at room temperature for 12 hours. After addition of water, the organic phase is separated after settling out, washed with a 2 normal hydrochloric acid solution and then with water until a pH of the washings equal to 7 is obtained. After drying over sodium sulfate, the organic phase is evaporated off. The resulting solid is dispersed in 10 ml of hexane and drained. 1.1 g of the expected compound are thus obtained in the crude state. The latter is recrystallized from 140 ml of ethanol (12 hours at −20° C.) and then drained and dried. 0.77 g of the expected compound is obtained, that is to say a yield of 46.7%. ′This compound has a melting point of between 225 and 227° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([OH:11])[CH3:10].[CH2:12](C1C([N+]([O-])=O)=CC=CC=1S(O)(=O)=O)[C@H:13]1[O:15][CH2:14]1.[H-].[Na+].O>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]([O:11][CH2:12][C@H:13]1[CH2:14][O:15]1)[CH3:10]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1C[C@@H]1CO1
Reactant: Cc1cccc([C@@H](C)O)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc([C@@H](C)OC[C@H]2CO2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(1R)-1-(2-bromo-3-methylphenyl)ethanol (2.00 g, 9.30 mmol) obtained in Example 4(4a) and (R)-glycidyl 3-nitrobenzene sulfonic acid (3.13 g, 12.1 mmol) were dissolved in N,N-dimethyl formamide (45 mL), added with sodium hydride (608 mg, content 55%, 14.0 mmol), and stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. After that, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (1.51 g, yield 60%).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:31](Br)[CH:32]=[CH2:33].O>CN(C=O)C.CCCCCC.CCOC(C)=O>[CH2:33]([N:4]1[C:5]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[O:23][CH2:24][C@H:3]1[CH2:1][CH3:2])[CH:32]=[CH2:31]
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1CC
Temperature: 50 °C
Yield: 86 %

Procedure:
To a suspension of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.250 g, 0.734 mmol) and K2CO3 (0.507 g, 3.67 mmol) in 3 mL DMF was added allyl bromide (0.636 mL, 7.34 mmol) and the reaction mixture was heated to 50° C. for 4 h. The reaction mixture was poured into 40 mL water and extracted with EtOAc (2×30 mL). The extracts were washed with 40 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) afforded 0.24 g (86% yield) of (3R)-4-allyl-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. Rf0.6 (9:1 hexane:EtOAc); 1H NMR (400 MHz, CDCl3) δ7.41 (d, 1H, J=9.0), 7.21 (d, 1H, J=9.0), 7.18 (s, 1H), 5.96–5.85 (m, 1H), 5.47 (septet, 1H, J=6.1), 5.25 (dd, ABX, 1H, J=17.1, 1.1), 5.20 (d, 1H, J=10.1), 4.31 (dd, ABX, 1H, J=10.7, 2.2), 4.03 (dd, ABX, 1H, J=16.8, 5.0), 3.95–3.89 (m, 2H), 3.27–3.22 (m, 1H), 1.69–1.59 (m, 2H), 1.38 (d, 3H, J=6.1), 1.37 (d, 3H, J=6.1), 0.97 (t, 3H, J=7.5).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C[C:38]([N:40](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:38]#[N:40])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(Br)cc4c3=O)cc2)CCC1
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(C#N)cc4c3=O)cc2)CCC1
Temperature: 150 °C
Yield: 54 %

Procedure:
{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (92 mg, 0.17 mmol), zinc (II) cyanide (40 mg, 0.34 mmol) and tetrakis(triphenyphosphine)palladium(0) (20 mg, 0.017 mmol) were suspended in DMA (2 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 30 min. The resulting mixture was allowed to cool to RT, partitioned between ethyl acetate (40 mL) and water (20 mL) and the phases separated. The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (45 mg, 54%). LCMS (Method B): RT=4.76 min, [M+Na]+=515.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:3]1[C:2]([F:1])=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: OCc1ccc2c(c1F)CCCC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1c(CCl)ccc2c1CCCC2

Procedure:
The alcohol 47.7 (0.5 g, 2.77 mmol) is dissolved in anhydrous DCM (50 mL). Thionyl chloride (302 μL, 4.2 mmol) is slowly added dropwise to the above solution. The resulting mixture is stirred until TLC confirms the consumption of the starting material. The organic solvent is removed in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford chloride 47.8.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)(=[O:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(COC)OC.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])(=[O:22])[CH3:21]
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2Br)cc1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccccc2C(C)=O)cc1
Temperature: 100 °C

Procedure:
N-(2-Bromo-phenyl)4-methoxy-benzenesulfonamide (0.34 g, 0.99 mmol) was dissolved in dimethoxyethane (4 mL) and tetrakis(triphenylphosphine)palladium (0) (0.23 g, 0.2 mmol) was added. 2-acetylphenylboronic acid (0.16 g, 0.99 mmol), dissolved in ethanol (1 mL), was added, followed by aqueous sodium carbonate (4.2 mL, 2 M). The reaction mixture was heated at 100° C. for 14 hours. The mixture was diluted with a saturated, aqueous sodium chloride solution (200 mL) and extracted with dichloromethane (4×30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield a residue. The crude product was purified by silica gel chromatography (1:9 to 3:7 ethyl acetate:hexane) to afford the title product.
Reaction SMILES: C(OC(=O)[C@H](OC1C=C(Cl)N=C(SCC2C=CC=C(F)C=2F)N=1)C)C.C([O:28][C:29](=[O:57])[C@H:30]([O:32][C:33]1[CH:38]=[C:37]([NH:39][S:40]([N:43]2[CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])[N:36]=[C:35]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:34]=1)[CH3:31])C.[OH-].[Na+].Cl>CO>[N:43]1([S:40]([NH:39][C:37]2[N:36]=[C:35]([S:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[F:56])[N:34]=[C:33]([O:32][C@H:30]([CH3:31])[C:29]([OH:57])=[O:28])[CH:38]=2)(=[O:42])=[O:41])[CH2:46][CH2:45][CH2:44]1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 23) (0.24 g) in methanol (1 mL) was added 1M aqueous sodium hydroxide (1 mL). The resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was acidified using 2M aqueous HCl, then extracted with EtOAc (×2). The combined organics were washed with brine then dried (MgSO4), filtered and evaporated. The resulting oil was triturated with DCM/iso-hexane to give the title compound was a white solid. Yield: 0.20 g
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-amino-2-chlorobenzonitrile (5.02 g, 32.9 mmol) in dichloromethane (80 mL) was added N,N-diisopropylethylamine (17.0 mL, 97.8 mmol) and methanesulfonyl chloride (3.0 mL, 38.8 mmol) at −78° C. The reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was quenched with 1 N hydrochloric acid. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 50:50 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-oxopropylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (STEP J), 400 mg 10% Pd/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR(200 MHz, CDCl3) δ 1.10(t, CH2CH2CH3), 1.92(m, CH2CH2CH3), 1.9-2.6(m, 3-CH2 and 4-CH2), 2.40(s, CH3C(O)CH2), 3.86(s, OCH3), 3.90(s, 2 OCH3), 4.12(t, OCH2CH2CH3), 4.42(s, CH3C(O)CH2), 5.10-5.28(m, 2-CH and 5-CH), 6.64(s, 5-ArH), 7.35 and 7.47(2 d, 2-ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CN1CCOCC1.OC1C2N=NNC=2C=CC=1.CN(C)CCCN=C=NCC.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][NH:5][C:6]1[N:7]=[CH:8][C:9]2[C:15]([N:16]3[CH2:17][CH2:18][CH:19]([C:22]([N:32]4[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][OH:37])[CH2:30][CH2:31]4)=[O:24])[CH2:20][CH2:21]3)=[N:14][CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=C(O)C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1
Reactant: OCCN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C1CCN(c2nccc3nc(NCc4ccccc4Cl)ncc23)CC1)N1CCN(CCO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.5 %

Procedure:
1-[2-(2-Chloro-benzylamino)-pyrido[4,3-d]pyrimidin-5-yl]-piperidine-4-carboxylic acid 14 (50 mg, 0.13 mmol), 2-piperazin-1-yl-ethanol (17.0 mg, 0.13 mmol) and 4-Methylmorpholine (70 μL, 0.64 mmol) were dissolved in DMF (3 mL). To this mixture hydroxybenzotriazole (17.0 mg, 0.13 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide×HCl (24.0 mg, 0.13 mmol) were added and the mixture was stirred for 48 h at room temperature. Water was added to the mixture and the precipitate formed was filtered off and dried in vacuo. The residue was purified by silica chromatography (ethyl acetate/cyclohexane) to yield in a colorless solid (27.8 mg, 0.05 mmol, 43%) characterized as 15.
Reaction SMILES: [O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:7][CH2:6]1.[H][H]>[Pd].C(O)C>[OH:1][CH:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:3][O:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:9][CH2:10]1
Reactant: O=C(CO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](OCC(O)c2ccccc2)CC1

Procedure:
A mixture of 1 g of trans-2-[4-(2-oxo-2-phenyl-ethoxy)-cyclohexyl]-isoindole-1,3-dione and 0.1 g of 10% palladium on carbon in 100 mL of ethanol was stirred under 1 atm. of hydrogen overnight. The catalyst was filtered off and the filtrate concentrated to dryness under reduced pressure. Drying under vacuum gave 1.0 g of product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) 7.8 (m, 2H), 7.65 (t, 1H), 7.4-7.2 (m, 5H), 4.82 (d, 1H), 4.1 (m, 1H), 3.65 (m, 2H), 3.4 (m, 2H), 2.3 (dd, 2H), 2.2 (m, 2H), 1.8 (d, 2H), 1.4 (dd, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
Methyl 4-(methylamino)-3-nitrobenzoate (1.82 g, 8.66 mmol) was dissolved in a 1:1 ratio of tetrahydrofuran (THF) (41.4 mL) and water (41.4 mL). To this was added lithium hydroxide (1.817 g, 43.3 mmol) and the reaction stirred at r.t. for 16 h. The reaction mixture was cooled to 0° C. and acidified by the addition of 5M HCl (˜20 mL, until the pH reached ˜5)—a bright yellow precipitate formed, the slurry was filtered and the residue washed with distilled H2O (2×30 mL). The residue was collected and dried in vacuo at 50° C. to afford the product as a yellow solid (1.43 g, 7.29 mmol, 84% yield). This was used without further purification in the subsequent reactions.