Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32]C)=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].O.[OH-].[Li+]>C(#N)C.O.C1COCC1>[CH3:22][C@H:18]([O:17][C:15]1[CH:16]=[C:2]([O:1][C:24]2[N:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=2)[CH:3]=[C:4]([C:5]([NH:7][C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)=[O:6])[CH:14]=1)[CH2:19][O:20][CH3:21]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 53.7 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.226 g, 0.74 mmol), methyl 5-chloropyrazine-2-carboxylate (192 mg, 1.11 mmol) and potassium carbonate (205 mg, 1.48 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours. The solvent was removed in vacuo and water (30 mL) added. The mixture was acidified and extracted into ethyl acetate (3×50 mL), the combined organics washed with brine (30 mL), dried (MgSO4), filtered and reduced in vacuo to give a brown oil which was a mixture of the acid and methyl ester. Lithium hydroxide monohydrate (78 mg, 1.85 mmol) in water (2 mL) was added to the mixture of acid and ester (326 mg, 0.74 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous residue washed with ethyl acetate (20 mL) to remove impurities then acidified with 1M citric acid. The product was extracted into ethyl acetate (2×100 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow solid (0.17 g). m/z 428 (M+H)+
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([CH2:35][O:36]C(=O)C)=[O:34]>>[OH:36][CH2:35][C:33]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:34]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Agent: Cl
Product: O=C(NC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A159) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:48]>>[NH2:48][C:8]1[C:7]2[N:16]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:17][CH2:18][C:19]([NH:21][CH2:22][CH2:23][CH3:24])=[O:20])[C:6]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCNC(=O)CCn1c(CCC)nc2cnc3ccccc3c21
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCn1c(CCC)nc2c(N)nc3ccccc3c21

Procedure:
3-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide (3.5 g, 11 mmol) was treated with mCPBA (5.85 g, 32.4 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (2.76 g, 14.6 mmol) according to a modification of the method described in Part D of Example 8. When the reaction was complete, the organic layer was separated, washed with 10% aqueous sodium bicarbonate, and concentrated under reduced pressure. The crude product was purified as described in Part D of Example 8 to provide 1.026 g of 3-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide as beige needles, mp 157-158° C.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[OH:32])[CH2:11][CH2:10]1)C1C=CC=CC=1>COCCO.[Pd]>[ClH:1].[NH:9]1[CH:10]=[CH:11][CH:12]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH:23]([CH3:31])[CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[OH:32])[CH2:13][CH2:14]1
Reactant: CCCCCC(C)C(C)c1cc(O)c(C2=CCN(Cc3ccccc3)CC2)c(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: COCCO
Product: CCCCCC(C)C(C)c1cc(O)c(C2C=CNCC2)c(OC)c1

Procedure:
The compound of Example XXVII (8.0 g) in 2-methoxyethanol was hydrogenated using 5% Pd on carbon as a catalyst and stopping the reaction after one equivalent was taken up. The product (5.3 g) had an m.p. of 192°-194° (83%).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([Cl:11])[CH:5]=2.Br[C:13]1[CH:14]=[N:15][N:16]([CH2:18][CH2:19][CH3:20])[CH:17]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[N:3]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][CH3:20])[CH:17]=2)[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([Cl:11])[CH:5]=2
Reactant: Clc1ccc2cc(Cl)[nH]c2c1
Reactant: CCCn1cc(Br)cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCn1cc(-n2c(Cl)cc3ccc(Cl)cc32)cn1
Temperature: 120 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a stirred solution of compound 2 (350 mg, 1.89 mmol) in toluene (10 mL) under inert atmosphere were added 4-bromo-1-propyl-1H-pyrazole (Intermediate B; 422 mg, 2.27 mmol), potassium phosphate (1 g, 4.72 mmol), N,N′-dimethylethylene diamine (66.7 mg, 0.75 mmol) and CuI (36 mg, 0.18 mmol) at RT; heated to 120° C. and stirred for 12 h in a sealed tube. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 5-7% EtOAc/Hexanes to afford compound 3 (200 mg, 36%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.63 (s, 1H), 7.59 (s, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J=9.0 Hz, 1H), 6.55 (s, 1H), 4.18 (t, J=7.0 Hz, 2H), 2.02-1.97 (m, 2H), 0.98 (t, J=7.5 Hz, 3H); LC-MS (ESI): 59.4%; m/z 294.2 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 4.66 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:28]([C:33]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3′-Chloro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.38 min; [M+H]+=490.9.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9][C:8]1=[N:13][N:14]=C(C)C)=[O:5])[CH3:2].Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][S:9][C:8]1=[N:13][NH2:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)CSC1=NN=C(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)CSC1=NN
Yield: 51.5 %

Procedure:
To 2.0 g of 3-ethoxycarbonylmethyl-2-isopropylidenehydrazonothiazilidin-4-one obtained in step (1) of Example 9 was added 30 ml of 0.5N hydrochloric acid, and the mixture was subjected to steam distillation for 15 minutes. The reaction mixture obtained was cooled, the resulting precipitates were distilled off, and the filtrate was concentrated under reduced pressure. To the residue formed were added a saturated sodium hydrogencarbonate solution and chloroform to distribute the residue between them. The organic layer was washed three times with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue formed was charged on silica gel column chromatography and eluted with a mixture of chloroform and ethyl acetate at 4:1 by volume to obtain 870 mg of 3-ethoxycarbonylmethyl-2-hydrazonothiazolidin-4-one.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([NH:13][CH3:14])=[C:7]([NH2:15])[C:6]=1[CH3:16])(=O)C.CO[C:19]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1)=O.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O1CCOCC1>[OH:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[N:13]([CH3:14])[C:19]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:35][CH:36]=3)=[N:15][C:7]=2[C:6]=1[CH3:16]
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(O)c(C)c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
A mixture of 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine [prepared as described in step (j) above], 2.7 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidine-2,4-dione [prepared as described in step 2(g) of Preparation 2], 5 ml of 1,4-dioxane and 25 ml of concentrated aqueous hydrochloric acid was heated under reflux for 2 days. At the end of this time, the reaction mixture was added to ice-water and the resulting mixture was neutralized by the addition of sodium hydrogencarbonate. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. Fractions containing the title compound were collected and the solvent was removed by distillation under reduced pressure, to give a red residual oil. 150 ml of diethyl ether were added to the oil, and the mixture was agitated ultrasonically for 5 minutes. The precipitate which separated out was collected by filtration and dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of between about 10 ml and 20 ml by evaporation under reduced pressure. 200 ml of ethyl acetate were added to the concentrate, and the mixture was agitated ultrasonically for 20 minutes. The precipitate which separated out was collected by filtration, to give 0.52 g of the title compound, melting at 240-244° C. and having an Rf value=0.44 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][O:27]C4CCCCO4)=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:34]>CCO>[ClH:34].[ClH:34].[CH:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]3[N:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[C:24]([NH:26][OH:27])=[O:25])=[N:20][CH:21]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCCC3CCCCC3)C2)cn1)NOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: O=C(/C=C/c1cnc(N[C@@H]2CCN(CCCC3CCCCC3)C2)cn1)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-[5-({(3R)-1-(3-cyclohexylpropyl)-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (151 mg) in EtOH (0.75 mL) was added 2N—HCl solution in EtOH (0.75 mL) and the reaction mixture was stirred for 2 hours at ambient temperature. The mixture was evaporated and acetone was added. The resulting solid was collected by filtration to give (2E)-3-[5-({(3R)-1-(3-cyclohexylpropyl)-3-pyrrolidinyl}amino)-2-pyrazinyl]-N-hydroxyacrylamide dihydrochloride (117 mg).
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[Br:27]Br>>[Br:27][C:24]1[CH:23]=[C:22]([OH:25])[C:21]([OH:26])=[CH:20][C:19]=1[C:9]1[C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][C:14]=2[C:2]([Br:1])=[C:3]2[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Oc1ccc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O
Reactant: BrBr
Product: Oc1cc(Br)c(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1O

Procedure:
Prepared from 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-benzene-1, 2-diol (Example 43) according to the procedure of Example 58. White solid: mp 138-140° C.: MS (EI): [M+], 2 bromine isotope pattern, 498, 500, 502; Anal. Calc. for C22H12Br2O2S: C, 52.83, H, 2.42, N, 0.00. Found: C, 52.17, H, 2.71, N, 0.05.
Reaction SMILES: [OH:1]C1CCN(C)CC1.FC1C=CC(C#N)=CC=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:33]=[CH:32][C:29]([C:30]#N)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=[O:1])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CN1CCC(Oc2ccc(C#N)cc2)CC1
Reactant: CN1CCC(O)CC1
Agent: N#Cc1ccc(F)cc1
Product: CN1CCC(Oc2ccc(C=O)cc2)CC1

Procedure:
Synthesized from 4-hydroxy-1-methylpiperidine and 4-fluorobenzonitrile according to an analogous synthetic method to Preparation Example 15, 4-(1-methylpiperidin-4-yloxy)benzonitrile (500 mg) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (350 mg).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].[K+].Br.Cl>CN(C=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2)cc1
Agent: Br
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4′-{[tert-butyl(dimethyl)silyl]oxy}-1,1′-biphenyl-4-carbaldehyde (320 mg, 1.03 mmol), anhydrous KF (120 mg, 2.06 mmol) and 48% aqueous HBr (35 ul, 0.31 mmol) in 6 mL dry DMF was stirred at room temperature under N2 for 1 h. TLC indicated starting material present and therefore more 48% aqueous HBr (35 uL, 0.31 mmol) was added into the reaction and the mixture was continued to stir for 1.5 h. The mixture was then poured, with cooling, into 1 N aqueous HCl (30 mL). The aqueous mixture was extracted with EtOAc (3×). The combined extracts were washed with saturated NaCl solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the product (100%) which was used directly in the next step. 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.43 Hz), 7.63 (2H, d, J=8.46 Hz), 7.83 (2H, d, J=8.16 Hz), 7.94 (2H, d, J=8.02 Hz), 9.79 (1H, s), 10.01 (1H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9](O)[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O.C(#N)C>CCOCC>[CH2:1]([O:4][C:5]1[N:10]=[C:9]([Cl:24])[C:8]([F:12])=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ncc(F)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Solvent: CCOCC
Product: C=CCOc1ncc(F)c(Cl)n1
Temperature: 80 °C

Procedure:
A 250 mL round bottom flask was charged with 2-(allyloxy)-5-fluoropyrimidin-4-ol 4.96 g, 29.2 mmol), N,N-dimethylaniline (5.45 mL, 43.0 mmol), phosphorous oxychloride (3.30 mL, 35.4 mmol), and acetonitrile (60 mL). The resulting solution was heated at 80° C. for 1 h. After cooling to room temperature, the crude material was diluted with Et2O (300 mL) and was washed with 1.0 M aqueous NaH2PO4 (150 mL×2) and saturated aqueous NaCl (150 mL). The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 2-(allyloxy)-4-chloro-5-fluoropyrimidine contaminated with N,N-dimethylaniline (6.71 g, 72.5% pure, 89% calcd.) as a brown oil: 1H NMR (300 MHz, DMSO-d6) δ 8.78 (bs, 1H), 6.04 (m, 1H), 5.38 (d, J=16.8 Hz, 1H), 5.26 (d, J=10.3 Hz, 1H), 4.82 (dd, J=0.8, 5.3 Hz, 2H); MS (EI) m/z 187 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O)[CH:18]([CH3:20])[CH3:19].C(OCC)(=O)C>O1CCCC1.O>[CH2:17]([O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COc1ccccc1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccccc1OCC(C)C
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
In 30 ml of tetrahydrofuran is suspended 0.92 g of 60% sodium hydride. After dropping 5.0 ml of ethyl diethylphosphonoacetate thereinto at ambient temperature over a period of 5 minutes, the mixture thus obtained is stirred at 40° C. for 30 minutes. Then, a solution of 3.40 g of 2-isobutoxybenzaldehyde in 20 ml of tetrahydrofuran is dropwise added at ambient temperature over a period of 20 minutes, and the mixture thus obtained is stirred for one hour. The reaction mixture is added to a mixture of ethyl acetate and water, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to obtain 4.30 g of ethyl 3-(2-isobutoxyphenyl)-2-propenoate as a light yellow oily product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29].O>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:25]/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC/C=C/C(=O)O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-di-tert-butyl-4-mercaptophenol (II) (590 mg; 2.48 mmol) in dry ether (10 ml), triethylamine (303 mg; 3 mmol) was added, and a solution of ethyl 4-bromocrotonate (580 mg; 3 mmol) in dry ether (5 ml) was added while cooling with ice, followed by stirring at room temperature for 2 hours. The reaction mixture was combined with water (50 ml) and extracted with ether (50 ml). The extract was washed with water (50 ml) two times and concentrated under reduced pressure. The crude intermediate product as pale yellow oil was dissolved in ethanol (30 ml), 10 % sodium hydroxide solution (3 ml) was added thereto, and the resultant mixture was stirred at room temperature for 2 hours. To the reaction mixture, acetic acid (2 ml) was added, and the resulting mixture was concentrated under reduced pressure to make a volume of about 10 ml, which was extracted with ethyl acetate (50 ml). The extract was washed with water (50 ml) two times, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual oil was chromatographed on silica gel and eluted with ethyl acetate. The collected fractions were concentrated under reduced pressure, and the crystalline residue was recrystallized from n-pentane to give the objective compound (Ih) (270 mg). m.p., 104°-106° C. Yield, 34 %.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH3:29]C(O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:29])[CH:12]2[CH2:24][N:16]3[C:17]4[C:22]([CH:23]=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=S(=O)(NC1CCc2cc3ccccc3n2C1)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C1CCc2cc3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from Step 8 (3 g) in 100 mL of DMF were added 0.4 g of NaH (60% in mineral oil) and 1.2 mL of MeI. After stirring for 1 h at room temperature, 1 mL of AcOH was added and the mixture was concentrated under vacuum and the residue was dissolved in 200 mL of 1:1 hexane/EtOAc and filtered through a pad of silica gel. The filtrate was concentrated and the residue was swished from 2:1 hexane/EtOAc to give 2.5 g of the title product. 1H NMR (500 MHz, acetone-d6) δ 8.10 (m, 2H), 7.47 (m, 3H), 7.28 (d, 1H), 7.09 (dd, 1H), 7.02 (dd, 1H), 6.15 (s, 1H), 4.55 (m, 1H), 4.20 (m, 1H), 3.88 (t, 1H), 3.05-3.12 (m, 1H), 2.92-3.02 (m, 1H), 2.97 (s, 3H), 1.92-2.02 (m, 1H), 1.66 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:18]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CO
Reactant: COc1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cccc(OC)c1

Procedure:
A solution of 25.0 g (150 ml) of (3-methoxyphenyl)acetic acid in dry methanol (250 ml) was mixed with 2 ml of conc. sulfuric acid and heated under reflux for 16 h. The cooled reaction solution was concentrated in vacuo, added to ice-water and extracted four times with 70 ml of ethyl acetate each time. The combined organic extracts were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. Yield: 28.3 g (100%) of colorless oil
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH:55]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCC(O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CC(O)c2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
To a solution of 50 mg (0.31 mmol) of 1H-indole-7-carboxylic acid and 97 mg of TBTU (0.31 mmol) in 4 ml DMF, were added 0.27 ml (1.55 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 99 mg (0.31 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 2:1) to give 89 mg (61%) of a white solid. MS (ISP) 461.4 (M+H)+.