Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][PH:2](=[O:4])[CH3:3].[N:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.N#N.[CH2:20](O)C>>[CH2:11]=[O:12].[CH3:1][P:2]([CH2:20][N:8]1[CH2:9][CH2:10][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7]1)([CH3:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[PH](C)=O
Reactant: CCO
Agent: N#N
Product: C=O
Product: CC(C)(C)OC(=O)N1CCN(CP(C)(C)=O)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Dimethylphosphane oxide (2.25 g, 28.8 mmole, 1.09 eq.) and tert-butyl piperazine-1-carboxylate (14.93 g, 26.5 mmole, 1.0 eq.) were dissolved in 20 mL of anhydrous ethyl alcohol. The reaction mixture was sealed in a seal-tube with N2 atmosphere and stirred at 90 Celsius overnight. The reaction mixture was then cooled to room temperature and rotaevaporate to remove volatile components. The light yellow thick oil obtained was purified via column chromatography (elution sequence: 100% hexane—10% EtOAc/hexane—100% EtOAc—10% MeOH/EtOAc/sat.NH3) to yield 1.01 g of the desired compound as white solid. MS (LC/MS): 299.2 [M+Na]
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][O:15][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCCO)cc1
Reactant: NS(=O)(=O)Cl
Product: COc1ccc(OCCOS(N)(=O)=O)cc1
Yield: 54 %

Procedure:
The title compound was prepared by procedures of Example 16 from sulfamoyl chloride and 2-(4-methoxyphenoxy)ethanol in 54% yield as an off-white solid, mp 84°-87° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].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>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([S:16][CH3:15])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Fc1ccc(-c2ccccc2Br)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1ccc(-c2ccccc2-c2ccc(F)cc2)cc1
Yield: 93.4 %

Procedure:
Under nitrogen, 200 mg of Pd(PPh3)4 was added to a stirred solution of 500 mg (2.0 mmol) of 1-bromo-2-(4-fluorophenyl)benzene (Step 1) and 500 mg (3.0 mmol) of 4-methylthiophenylboronic acid (Step 2) in 7 mL of toluene, 7 mL of ethanol and 7 mL of 2M Na2CO3. After vigorous stirring at reflux overnight, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters LC-2000) with ethyl acetate/hexane (2:98) as the eluent gave 550 mg of 1-(4-fluorophenyl)-2-[4-(methylthio)phenyl]benzene as a semi-solid: NMR (CDCl3) δ 2.46 (s, 3H), 6.92 (t, J=8 Hz, 2H), 7.02-7.14 (m, 6H), 7.37-7.42 (m, 4H). MS (EI): m/e (rel intensity) 294 (100), 279 (39), 277 (56), 246 (74), 227 (40), 190 (43), 190 (38), 140 (44).
Reaction SMILES: O1CCOCC1.[CH3:7][N:8]1[CH2:16][C:15]2[C:10](=[C:11]([N+:26]([O-:28])=[O:27])[CH:12]=[CH:13][C:14]=2B2OC(C)(C)C(C)(C)O2)[C:9]1=[O:29].[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O>[CH3:30][C:31]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:36][CH2:35][C:34]([C:14]2[CH:13]=[CH:12][C:11]([N+:26]([O-:28])=[O:27])=[C:10]3[C:15]=2[CH2:16][N:8]([CH3:7])[C:9]3=[O:29])=[CH:33][CH2:32]1
Reactant: CCOC(=O)C1(C)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CN1Cc2c(B3OC(C)(C)C(C)(C)O3)ccc([N+](=O)[O-])c2C1=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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CC=C(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 70 °C
Yield: 84.3 %

Procedure:
A mixture of dioxane and water (15 mL, 4:1) was degassed for 30 min. 2-Methyl-7-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-isoindol-1-one (373 mg, 1.19 mmol), ethyl 1-methyl-4-{[(trifluoromethyl)sulfonyl]oxy}cyclohex-3-ene-1-carboxylate (Compound 282E, 300 mg, 0.92 mmol), Pd (PPh3)4 (106 mg, 0.092 mmol), and cesium carbonate (747 mg, 2.3 mmol) were then added. The reaction mixture was heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and concentrated to dryness, the residue was purified by column chromatography (SiO2, 5% ethyl acetate/dichloromethane) to give 278 mg (yield: 77%) of the desired compound. 1H NMR (CDCl3, 300 MHz): δ=1.26 (t, J=6.9 Hz, 3 H), 1.76-1.78 (m, 1 H), 2.07-2.22 (m, 3 H), 2.40 (m, 1 H), 2.80-2.42 (m, 1 H), 3.21 (s, 3 H), 4.15 (q, J=6.9 Hz, 2 H), 5.92 (s, 1 H), 7.44 (d, J=8.5 Hz, 1 H), 7.70 (d, J=8.5 Hz, 1 H).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:29]5[CH:30]=[CH:31][N:32]=[CH:33][C:28]=5[N:27]([CH:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])(=O)C.[Li+].[OH-]>C1COCC1.CO.O>[CH:34]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[N:16]=[CH:15][C:14]([N:11]5[CH2:12][CH2:13][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:9][CH2:10]5)=[CH:19][CH:18]=4)[N:22]=[CH:23][C:24]=3[C:29]3[CH:30]=[CH:31][N:32]=[CH:33][C:28]2=3)[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(CO)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of compound 189 (˜0.5 mmol) in THF/methanol/H2O (3:1:1, 10 mL) was added 12 mg of LiOH and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated and the residue was dissolved in dichloromethane then washed with water and brine then dried. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with CH2Cl2:methanol:NH4OH (400:10:1) to give compound 188 as a yellow solid (150 mg, 63% in two steps). 1H NMR (500 MHz, DMSO-d6) δ 9.82 (1H, s), 9.27 (1H, s), 9.01 (1H, s), 8.44 (1H, d, J=5 Hz), 8.21 (1H, d, J=10 Hz), 8.07 (1H, d, J=2 Hz), 8.04 (1H, d, J=5 Hz), 7.52 (1H, dd, J=10 Hz, J=2 Hz), 5.37 (1H, p, J=10 Hz), 4.65 (1H, t, J=5 Hz), 4.15 (2H, d, J=5 Hz), 3.65 (2H, m), 3.53 (2H, m), 3.15 (4H, m), 2.40 (2H, m), 2.08 (4H, m), 1.78 (2H, m) ppm; LCMS-ESI (POS), M/Z, M+1: Found 472.2, Calculated 472.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5](Br)=[CH:4][N:3]=1.[C:24]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)(OC(C)(C)C)=O>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([CH3:22])([OH:21])[CH3:20])[CH:15]=3)[CH:10]=[N:9]2)[C:5]([C:34]2[CH:33]=[N:32][N:31]([CH3:24])[CH:35]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(O)C#Cc1ccc2cnn(-c3nc(N)ncc3Br)c2c1
Product: Cn1cc(-c2cnc(N)nc2-n2ncc3ccc(C#CC(C)(C)O)cc32)cn1

Procedure:
4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol (0.075 g) was reacted 1-Boc-4-pyrazoleboronic acid pinacol ester via Suzuki Coupling to afford 9.5 mg of 4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol following reverse phase hplc purification. MS (Q1) 360. 1H NMR (400 MHz, DMSO) delta 12.71 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (s, 2H), 5.45 (s, 1H), 1.47 (s, 6H).
Reaction SMILES: ClCCl.[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O>[O:4]=[C:5]1[N:9]([CH2:10][CH2:11][CH2:12][C:13]([O:15][Cl:23])=[O:14])[C:8]2[CH:16]=[CH:17][CH:18]=[CH:19][C:7]=2[NH:6]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCn1c(=O)[nH]c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCCn1c(=O)[nH]c2ccccc21)OCl
Temperature: 10 °C

Procedure:
Dichloromethane (3772 L) and then 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (525 kg; 2.4 kmol) were charged to a stirred-tank reactor, followed by N,N-dimethylformamide (21 L). The resulting mixture was cooled to 10° C. Afterward, oxalyl chloride (326.8 kg)) was dosed at 10-15° C. over 2-3 hours while stirring. The resulting mixture was then stirred at 15-20° C. for an additional 1-3 hours. All the above steps were conducted under a N2 atmosphere. Conversion was checked by in-process control (“IPC”).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.[N:16]1([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[F-].[Na+].O>C(Cl)Cl>[OH:4][CH:2]([CH3:3])[CH2:1][N:19]1[CH2:20][CH2:21][N:16]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17][CH2:18]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CC1CO1
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)CN1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of propylene oxide (4.0 mL, 57 mmol) in DCM (160 mL) was added 2.0 M of trimethylaluminum in toluene (27 mL, 54 mmol) at −78° C. under N2. After being stirred at that temperature for 10 min, a solution of benzyl piperazine-1-carboxylate (from Aldrich, 9 mL, 40 mmol) in DCM (60 mL) was added. The resulting reaction mixture was stirred at −78° C. for 30 min. The reaction was then allowed to warm up to 0° C., stirring for another 30 min. To the reaction mixture was added sodium fluoride (8.2 g, 200 mmol) in one portion, followed by water (5.2 mL, 290 mmol) slowly and periodically at 0° C. The resulting suspension was rapidly stirred for 1 h at 0° C. and filtered through a short column of Celite and the column was subsequently washed with DCM (120 mL). The combined filtrates were dried over Na2SO4, concentrated and purified on silica gel (eluting with 0-10% MeOH in DCM) to provide the desired product (9.6 g, 76%). LCMS calculated for C15H23N2O3(M+H)+: m/z=279.2; Found: 279.3. 1H NMR (500 MHz, DMSO-d6): δ 7.39˜7.31 (5H, m), 8.07 (2H, s), 4.29 (1H, J=4.0 Hz), 3.75 (1H, m), 3.38 (4H, br s), 2.38 (4H, m), 2.24 (1H, dd, J=12.5 and 7.0 Hz), 2.17 (1H, dd, J=12.5 and 7.0 Hz), 1.04 (3H, d, J=6.0 Hz) ppm.
Reaction SMILES: ClC1C=CC(O)=C(C2C=NN3C=CC=NC=23)C=1.[NH2:18][C:19]1[C:23]2[CH:24]=[C:25]([C:28]3[C:29](=[O:62])[N:30]([C:34]4[C:39]([F:40])=[CH:38][C:37]([S:41]([N:44](CC5C=CC(OC)=CC=5OC)[C:45]5[S:49][N:48]=[CH:47][N:46]=5)(=[O:43])=[O:42])=[C:36]([F:61])[CH:35]=4)[CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:27][C:22]=2[O:21][N:20]=1>>[NH2:18][C:19]1[C:23]2[CH:24]=[C:25]([C:28]3[C:29](=[O:62])[N:30]([C:34]4[C:39]([F:40])=[CH:38][C:37]([S:41]([NH:44][C:45]5[S:49][N:48]=[CH:47][N:46]=5)(=[O:43])=[O:42])=[C:36]([F:61])[CH:35]=4)[CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:27][C:22]=2[O:21][N:20]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(-n3cccc(-c4ccc5onc(N)c5c4)c3=O)cc2F)c(OC)c1
Agent: Oc1ccc(Cl)cc1-c1cnn2cccnc12
Product: Nc1noc2ccc(-c3cccn(-c4cc(F)c(S(=O)(=O)Nc5ncns5)cc4F)c3=O)cc12
Yield: 23 %

Procedure:
Following the procedure as described in EXAMPLE 44, making non-critical variations to replace 4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenol with 4-(3-(3-aminobenzo[d]isoxazol-5-yl)-2-oxopyridin-1(2H)-yl)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, 4-(3-(3-aminobenzo[d]isoxazol-5-yl)-2-oxopyridin-1(2H)-yl)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide was obtained as a colorless solid in 23% yield (0.04 g): 1H NMR (300 MHz, DMSO-d6) δ 8.22 (d, J=1.4 Hz, 1H), 8.04 (s, 1H), 7.82-7.67 (m, 5H), 7.46 (d, J=8.8 Hz, 1H), 6.51 (dd, J=6.9, 6.9 Hz, 1H), 6.45 (br s, 2H); MS (ES+) m/z 502.7 (M+1).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20].O>CN(C)C=O>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/COc1c(I)cc(I)cc1I
Temperature: 50 °C
Yield: 87 %

Procedure:
A mixture of triiodophenol (10.0 g, 21.2 mmol), milled potassium carbonate (3.1 g, 22.5 mmol, 1.06 eq) and geranyl bromide (4.0 ml, 20.2 mmol) in dimethyl formamide (25 ml) was heated to 50° C. for 2 hrs and cooled. The mixture was poured into 300 ml of water and extracted with ethyl acetate. The ethyl acetate extract was filtered through a short pad of silica gel, then alumina, eluting with ethyl acetate-hexanes (1:1). The eluent was concentrated under high vacuum to give the product in 87% yield as an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][CH:22]([OH:25])[CH2:23]O)=[CH:18][C:17]=3[O:28][CH3:29])[N:12]=2)[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].CC[N:32](C(C)C)C(C)C.CS(Cl)(=O)=O.[C:44]([OH:48])(=O)[CH2:45][OH:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[OH:46][CH2:45][C:44]([NH:32][CH2:23][CH:22]([OH:25])[CH2:21][O:20][C:19]1[CH:26]=[CH:27][C:16]([C:13]2[N:12]=[C:11]([C:7]3[S:8][C:9]([CH3:10])=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:6]=3)[O:15][N:14]=2)=[C:17]([O:28][CH3:29])[CH:18]=1)=[O:48]
Reactant: O=C(O)CO
Reactant: COc1cc(OCC(O)CO)ccc1-c1noc(-c2cc(CC(C)C)c(C)s2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CS(=O)(=O)Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: COc1cc(OCC(O)CNC(=O)CO)ccc1-c1noc(-c2cc(CC(C)C)c(C)s2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.7 %

Procedure:
To a solution of rac-3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-3-methoxy-phenoxy}-propane-1,2-diol (400 mg, 0.956 mmol) and DIPEA (257 mg, 1.99 mmol) in THF (40 mL), methanesulfonylchloride (125 mg, 1.095 mmol) dissolved in THF (10 mL) is added at −10° C. The reaction is allowed to warm to rt and is stirred for 15 h. Another portion of methanesulfonylchloride (30 mg, 0.258 mmol) in THF (2 mL) and DIPEA (128 mg, 0.993 mmol) is added and stirring is continued for 24 h. The mixture is evaporated and the residue is dissolved in 7 N NH3 in MeOH (17 mL). The resulting solution is stirred at 70° C. for 5 h before it is evaporated. The remaining residue is dissolved in DMF (15 mL) and glycolic acid (110 mg, 1.45 mmol), DIPEA (257 mg, 1.99 mmol) and TBTU (370 mg, 1.15 mmol) is added. The mixture is stirred at rt for 5 h, evaporated and the residue is purified on prep. TLC plates with EA to give 2-hydroxy-N-(2-hydroxy-3-{4-[5-(4-isobutyl-5-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-3-methoxy-phenoxy}-propyl)-acetamide (135 mg) as colourless foam; LC-MS: tR=0.95 min, [M+1]=476.29; 1H NMR (D6-acetone): δ 7.92 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.57 (s br, 1H), 6.77 (d, J=2.3 Hz, 1H), 6.71 (dd, J=2.3, 8.8 Hz, 1H), 4.74-4.67 (m, 2H), 4.15-4.07 (m, 3H), 3.99 (d, J=5.0 Hz, 2H), 3.93 (s, 3H), 3.66-3.57 (m, 1H), 3.48-3.39 (m, 1H), 2.52 (d, J=7.0 Hz, 2H), 2.49 (s, 3H), 1.95 (hept, J=7.0 Hz, 1H), 0.95 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:13][CH:12]([F:14])[CH2:11]1)=[O:9].[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([NH:30][C:31]3[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=3)=[O:29])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([F:14])[CH2:13]1)=[O:9]
Reactant: Cn1ccc(N)n1
Reactant: CC1(C)Cc2c(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)cc(C(=O)O)cc2O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To a solution of 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid (1.360 g, 3.363 mmol), 3-amino-1-methyl-pyrazole (653 mg, 6.730 mmol), and triethylamine (0.94 ml, 6.730 mmol) in 20 mL of DCE was added HATU (2.56 g, 6.730 mmol). The mixture was stirred at 60° C. for 2 hr, quenched with water, and extracted with 3×CHCl3. The combined organic layer was washed with 2×H2O, dried with Na2SO4, and concentrated to provide an oil that was purified by SFC to give a white solid (874 mg, 54% yield). 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1 H) 8.20 (d, J=2.02 Hz, 1 H) 7.24-7.33 (m, 2 H) 7.15-7.22 (m, 1 H) 7.09 (dd, J=10.86, 2.27 Hz, 1 H) 6.82 (d, J=2.27 Hz, 1 H) 5.37 (d, J=56.84 Hz, 1 H) 4.62-4.79 (m, 1 H) 4.53 (dd, J=12.13, 1.77 Hz, 2 H) 4.27-4.42 (m, 1 H) 3.80 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C24H23F2N5O4 m/z 484.20 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:10])[NH:2]2.[C:20]([O:27][CH3:28])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O-])=[O:24]>>[CH3:28][O:27][C:20](/[CH:21]=[CH:22]\[C:23]([N:2]1[C@H:3]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:10])[CH2:4][C@H:5]2[C@@H:1]1[CH2:8][CH2:7][CH2:6]2)=[O:24])=[O:26]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: CCCCCCCCOC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Product: CCCCCCCCOC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)/C=C\C(=O)OC

Procedure:
This compound was obtained analogously to the method described in Example 1 from n-octyl (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate and monomethyl maleate. MS (DCI) =380 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.CCN(CC)CC.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:37]([C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)(=[O:39])=[O:38])[N:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of NEt3 (triethylamine) and 230 mg of 4-methyl-benzenesulphonic acid chloride are mixed together then the reaction medium is agitated at ambient temperature for approximately 30 minutes. Then 2 ml of water is added, followed by extracting with 2×5 ml of methylene chloride, washing with 5 ml of water, drying, evaporating, impasting in ether, separating and drying. In this way 345 mg of expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([O:11]C)=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1.[OH-].[Na+].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[O:25])=[CH:19][CH:18]=2)[N:3]=1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN(C)c1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc(Cl)c1CC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
The thus obtained methyl {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate was dissolved in THF (1 mL) and treated with 1N NaOH (0.5 mL). The resulting biphasic mixture was stirred at room temperature for 14 hours at which time it was poured into water. The separated aqueous phase was washed with EtOAc and then acidified with 1N HCl and back extracted with EtOAc. The combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was dissolved in a minimum volume of THF to which n-hexane was added. The separated precipitate was collected by suction, rinsed with n-hexane, and dried under vacuum to give {4-chloro-6-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetic acid (0.038 g, 40% yield) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36](=[O:39])[CH:37]=[CH2:38])=[C:30]([CH3:40])[CH:29]=1.ClCCl>C(O)C>[O:23]1[CH2:27][CH2:26][O:25][CH:24]1[C:28]1[C:33]([CH3:34])=[CH:32][C:31]([NH:35][C:36]([CH2:37][CH2:38][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:5][CH2:6]2)=[O:39])=[C:30]([CH3:40])[CH:29]=1
Reactant: C=CC(=O)Nc1cc(C)c(C2OCCO2)cc1C
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C2OCCO2)c(C)cc1NC(=O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
To a 500 mL round-bottom flask was added biphenyl-2-ylcarbamic acid piperidin-4-yl ester (17.0 g, 58 mmol) and N-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenyl)acrylamide (13.1 g, 52.9 mmol). Ethanol (150 mL) and dichloromethane (150 mL) were added to form a slurry. The reaction mixture was heated at 50° C. to 55° C. for about 24 hours and then cooled to room temperature. Most of the solvent was removed on a rotary evaporator, resulting in a thick slurry. Ethanol (reagent grade) was added to form a total volume of about 200 mL and the resulting mixture was heated to 80° C. and then cooled slowly to room temperature. The resulting thick white slurry was filtered, washed with ethanol (20 mL) and dried in vacuum to provide biphenyl-2-ylcarbamic acid 1-[2-(4-[1,3]dioxolan-2-yl-2,5-dimethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (23.8 g, about 98% purity) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11]([O:18][CH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:11]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]=[C:24]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:25]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1cc(COCc2ccccc2)ncn1
Reactant: Oc1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: c1ccc(COCc2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1

Procedure:
To a solution of 5-hydroxy indole (1.33 g, 10 mmol) and 4-benzyloxymethyl-6-chloro-pyrimidine (2.35 g, 10 mmol) in acetonitrile (20 mL) is added DBU. After 16 h at rt the solution is concentrated under reduced pressure. The residue is purified by FCC (EtOAc/Heptane from 0% to 40%) to give 5-(6-benzyloxymethyl-pyrimidin-4-yloxy)-1H-indole. MS (ESI) m/z 447.0 (M+1).