Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32](=[O:34])[CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32](=[O:34])[CH3:33])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 110 °C
Yield: 19.7 %

Procedure:
According to Scheme 14 Method A: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 0.61 mmol, 0.20 g, Example 20 Step 2), K2CO3 (10 eq, 6.10 mmol, 0.84 g) and chloroacetone (4 eq, 2.43 mmol, 0.20 mL) in THF (10 mL) was heated in a microwave at 110° C. during 30 min. After filtration and evaporation, the resulting crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/AcOEt 80/20 then washed with Et2O and was dried to afford 1-(4-chloro-2-fluorobenzyl)-5-(4-(2-oxopropoxy)phenyl)pyridin-2(1H)-one (0.12 mmol, 46 mg, 20%) as a white solid.
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:51](OC(=O)C)(=[O:53])[CH3:52].[Cl-].[NH4+]>>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=2)[C:13]2[N:14]=[CH:15][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][N:31]([C:51](=[O:53])[CH3:52])[C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:17][N:18]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(C)=O)cn2)cc1
Temperature: 25 °C

Procedure:
To dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg, 0.185 mmol), pyridine (45 μl, 0.556 mmol) and N,N-dimethylaminopyridine (2.3 mg, 0.0185 mmol) were added, and further acetic anhydride (52 μl, 0.556 mmol) was added, followed by refluxing for 3 hours. This was cooled to room temperature, followed by addition of saturated aqueous ammonium chloride solution, and passed through Whatman tube. The resulting organic phase was concentrated under reduced pressure, to obtain 1-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-ethanone as a crude product. To this, TFA (2 ml) and concentrated sulfuric acid (2 drops) were added, followed by stirring at 40° C. for 4 hours. After concentration of TFA under reduced pressure, water was added, followed by neutralization with 1M aqueous sodium hydroxide solution. After filtering the solid, dichloromethane (5 ml) was added, followed by stirring at room temperature for 30 minutes, and the solid was filtered off, to obtain the desired compound as a colorless solid (29.3 mg, yield 46%).
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:14]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)=[CH:21][C:20]=3[F:33])=[O:17])=[CH:13][C:12]([C:34]([CH3:37])([CH3:36])[CH3:35])=[N:11]2)[CH:5]=1.COC(=O)C1C=CC(N2C(NC(NC3C=CC(OC4C=CN=C(C)C=4)=CC=3F)=O)=CC(C(C)(C)C)=N2)=CC=1.[OH-].[K+]>CO.O>[C:34]([C:12]1[CH:13]=[C:14]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=3)=[CH:21][C:20]=2[F:33])=[O:17])[N:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:38])=[O:2])[N:11]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)c1
Agent: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C)c3)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(C(=O)O)c3)c(F)c2)ccn1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 3-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester (2.0 g, 4.12 mmol; prepared in a similar manner as described for 4-(3-tert-butyl-5-{3-[2-fluoro-4-(2-methyl-pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzoic acid methyl ester) in methanol, was added potassium hydroxide (692 mg, 12.4 mmol) in water. The mixture was stirred at 40° C. overnight, then cooled to room temperature. Methanol was evaporated at reduced pressure, and the aqueous residue neutralized to pH 7 by addition of 2N HCl. The white solid that formed was collected by filtration and dried in vacuo to give the title compound (1.9 g, 98%). 1H-NMR (DMSO-d6) δ 8.95 (s, 1H), 8.92 (s, 1H), 8.30 (d, J=5.7 Hz, 1H), 8.11-8.03 (m, 2H), 7.94 (d, 10.2 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.18 (J=14.1 Hz, 1H), 6.95 (d, J=12.9 Hz, 1H), 6.75 (m, 2H), 6.39 (s, 1H), 2.39 (s, 3H), 1.89 (s, 9H); MS LC-MS [M+H]+=504.2, RT=2.47 min.
Reaction SMILES: [CH3:1][Mg+].[Br-].FC(F)(F)S(O[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)(=O)=O.[NH4+].[Cl-]>C1COCC1.O>[CH2:10]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:1]
Reactant: C[Mg+]
Reactant: O=S(=O)(OCC1CCc2ccccc2O1)C(F)(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
MeMgBr (45.6 mL, 137 mmol, 3M in ether) was added to a mixture of the title compound from Step 2 (13.5 g, 45.6 mmol) and CuBr-Me2S (1.61 g, 7.74 mmol) in THF (150 mL) at −5° C. The reactions was stirred at rt for 2 h. It was then poured onto a solution of NH4Cl (55 g, 1.04 mol) in water (200 mL) and extracted with DCM (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.66 g, 90%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.09-7.02 (m, 2H), 6.82-6.78 (m, 2H), 3.93-3.87 (m, 1H), 2.84-2.72 (m, 2H), 2.02-1.96 (m, 1H), 1.81-1.61 (m, 3H), 1.04 (t, J=7.2 Hz, 3H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[OH:15])([CH3:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7]([C:4]([CH3:5])([CH3:6])[CH2:3][CH2:2][O:15]2)=[CH:12][CH:11]=1
Reactant: COc1ccc(C(C)(C)CCO)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OCCC2(C)C
Yield: 76.4 %

Procedure:
To a toluene (30 ml) solution of 2-(3-hydroxy-1,1-dimethylpropyl)-5-methoxyphenol (3.0 g, 14.3 mmol) was added catalytic amount of p-toluenesulfonic acid. The stirred mixture was refluxed for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/9 to furnish 2.1 g (75% yield) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[CH2:22]([OH:25])[CH2:23][CH3:24].[OH-].[Na+]>O>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH2:20][O:25][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCCC(CCCC1CO1)C(C)=O
Reactant: CCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOCC(O)CCCC(CCCCCCC(=O)O)C(C)=O
Reaction time: 4 h

Procedure:
A mixture of ethyl 8-acetyl-12,13-epoxytridecanoate (14.9 g., 0.05 mole), propanol (60 ml.), sodium hydroxide (6.0 g., 0.15 mole) and water (15 ml.) is stirred 4 hours at 40°-45° and then heated 1 hour on the steam bath. The mixture is cooled, treated with water (250 ml.) and extracted with ether. The aqueous solution is acidified with hydrochloric acid. The oily product is taken up in ether, washed with water, and dried over sodium sulfate. Evaporation of the ether leaves the title compound as a pale yellow oil. Purification is effected by column chromatography on silica gel with 2% methanol in chloroform as the eluant.
Reaction SMILES: [CH3:1][C:2]1[C:21]2[C@:16]([CH3:23])([CH2:17][CH2:18][C:19](=[O:22])[CH:20]=2)[C@@H:15]2[C@H:4]([C@H:5]3[C@:12]([CH3:24])([CH2:13][CH2:14]2)[C@@H:8]([C:9](=[O:11])[CH3:10])[CH:7]([CH2:25]SC2C=CC=CC=2)[CH2:6]3)[CH:3]=1.C1(C)C=CC=CC=1.CO.C[O:43]P(OC)OC>C(N(CC)CC)C>[OH:43][C@:8]1([C@:12]2([CH3:24])[C@H:5]([C@H:4]3[C@H:15]([CH2:14][CH2:13]2)[C@:16]2([CH3:23])[C:21](=[CH:20][C:19](=[O:22])[CH2:18][CH2:17]2)[C:2]([CH3:1])=[CH:3]3)[CH2:6][C:7]1=[CH2:25])[C:9](=[O:11])[CH3:10]
Reactant: COP(OC)OC
Reactant: CC(=O)[C@H]1C(CSc2ccccc2)C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C1C[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
6-Methyl-16-(phenylsulfenylmethyl)-pregna-4,6-diene-3,20-dione (VIA, Example 22, 150 mg), toluene (1.25 ml), methanol (0.216 ml), triethylamine (0.011 ml) and finally trimethylphosphite (0.076 ml) were added to a vial which was sealed, stirred and heated at 100° for 4.75 hr. The mixture was concentrated under reduced pressure to an oil which is TLC'd on silica gel eluting with acetone/methylene chloride (5/95) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.Br[C:10]1[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=[C:14]([Br:16])[CH:15]=1>>[Br:16][C:14]1[CH:15]=[C:10]([NH:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=2)[C:11](=[O:18])[N:12]([CH3:17])[CH:13]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: Cc1nccc(N)n1
Product: Cc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Yield: 52 %

Procedure:
Following Example 148a, 2.0 g of 162a and 4.0 g of 3,5-dibromo-1-methyl-pyridin-2(1H)-one were reacted to give 162b as a yellow solid (2.3 g, 50%). LCMS: [M+H]+ 357 1H NMR (500 MHz, DMSO) δ 9.20 (s, 1H), 8.78 (s, 1H), 8.26 (d, J=4.5, 1H), 7.68 (s, 1H), 7.18 (d, J=4.5, 1H), 3.59 (s, 3H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:6][CH:5]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)#[CH:24]>CCCCCCC>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:24]#[C:23][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)=[CH:8][CH:9]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OC(F)(F)F)cc2)cc1
Solvent: CCCCCCC
Product: Nc1ccc(C#Cc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-trifluoromethoxy-phenyl ester and 4-ethynyl-phenylamine. Chromatography eluent: heptane; yield (111 mg, 80%); 1H NMR δ (CDCl3): 7.5 (d, J=8.42 Hz, 2H), 7.33 (d, J=8.60 Hz, 2H), 7.18 (d, J=8.41 Hz, 2H), 6.62 (d, J=8.62 Hz, 2H), 3.82 (s, 2H); LCMS m/z 277.
Reaction SMILES: C(OC([N:8]1[CH2:32][CH2:31][C:12]2=[N:13][C:14]3[CH:15]=[C:16]([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[CH:17]=[CH:18][C:19]=3[C:20](=[O:21])[N:11]2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:16]2[CH:17]=[CH:18][C:19]3[C:20](=[O:21])[N:11]4[CH2:10][CH2:9][NH:8][CH2:32][CH2:31][C:12]4=[N:13][C:14]=3[CH:15]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(C#Cc4cccc(F)c4)ccc3c(=O)n2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c2ccc(C#Cc3cccc(F)c3)cc2nc2n1CCNCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl-8-(2-(3-fluorophenyl)ethynyl)-11-oxo-1,2,4,5-tetrahydro-[1,4]diazepino[7,1-b]quinazoline-3(11H)-carboxylate (1.3 g, 3.0 mmol) in DCM (30 mL) was added trifluoroacetic acid (15 mL). The mixture was stirred for 1 h at room temperature. Then the reaction mixture was concentrated and purified by silica gel chromatography to give the desired product. MS (ESI): 334 (MH+); 1H NMR (300 MHz, CDCl3) δ 8.26-8.23 (d, J=8.2 Hz, 1H), 7.77 (s, 1H), 7.59-7.55 (d, J=8.3 Hz, 1.5 Hz, 1H), 7.38-7.34 (m, 2H), 7.29-7.26 (m, 1H), 7.14-7.09 (m, 1H), 4.53-4.50 (t, J=3.6 Hz, 2H), 3.24-3.17 (m, 4H), 3.11-3.10 (t, J=4.5 Hz, 2H). mGluR5 PAM EC50: ++.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][O:35][C:36]2[CH:41]=[N:40][N:39]([CH2:42][C:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51]O)=[CH:47][CH:46]=3)=[O:44])[C:38](=[O:53])[CH:37]=2)=[N:32][CH:33]=1.P(Br)(Br)Br>>[Br:25][CH2:51][C:48]1[CH:49]=[CH:50][C:45]([C:43](=[O:44])[CH2:42][N:39]2[C:38](=[O:53])[CH:37]=[C:36]([O:35][CH2:34][C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][N:32]=3)[CH:41]=[N:40]2)=[CH:46][CH:47]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CBr)cc1
Reactant: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CO)cc1
Agent: BrP(Br)Br
Product: O=C(Cn1ncc(OCc2ccc(Cl)cn2)cc1=O)c1ccc(CBr)cc1

Procedure:
2-[2-(4-Bromomethyl-phenyl)-2-oxo-ethyl]-5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one is prepared following preparation 15c from 650 mg (1.69 mmol) 5-(5-chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 18c) and 0.16 mL (1.69 mmol) phosphorus tribromide.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:31])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:31][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:20][CH2:19][N:18]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])[CH2:17][CH2:16]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccc(C)cc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2CCC(c3cc(CC(=O)O)cc4ccc(F)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (70 mg, 0.2 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in water (1 mL) and the reaction mixture was stirred for 24 h at RT. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give [{6-fluoro-4-[1-(toluene-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (52 mg, 77%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.37 (br s, 1H), 7.94 (dd, J=8.8, 6.4 Hz, 1H), 7.88 (d, J=10.3 Hz, 1H), 7.66-7.73 (m, 3H), 7.50 (d, J=8.3 Hz, 2H), 7.33-7.42 (m, 2H), 3.79 (d, J=12.2 Hz, 2H), 3.71 (s, 2H), 1.90 (d, J=11.7 Hz, 2H), 1.69-1.82 (m, 1H); MS cald. for C24H25FNO4S [(M−H)−]: 440, obsd. 440.4.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:24][C@@H:6]2[C:7](=[O:23])[O:8][C:9]3[C@@H:10]4[CH2:17][CH2:16][C@H:15]([C@H:18]([CH3:21])[CH2:19][OH:20])[C@@:11]4([CH3:22])[CH2:12][CH2:13][C:14]=3[C@@:5]2([CH3:25])[CH2:4][CH2:3]1>C(Br)C=C.[Ag]=O>[CH3:7][O:8][CH2:9][O:1][C@@H:2]1[CH2:24][C@@H:6]2[C:7](=[O:23])[O:8][C:9]3[C@@H:10]4[CH2:17][CH2:16][C@H:15]([C@H:18]([CH3:21])[CH2:19][O:20][CH2:6][C:5]([CH3:14])=[CH2:4])[C@@:11]4([CH3:22])[CH2:12][CH2:13][C:14]=3[C@@:5]2([CH3:25])[CH2:4][CH2:3]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Agent: O=[Ag]
Solvent: C=CCBr
Product: C=C(C)COC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](OCOC)C[C@@H]1C(=O)O3
Reaction time: 12 h
Yield: 99 %

Procedure:
Compound 95 (7.6 mg, 0.019 mmol) obtained in Example 67 was dissolved in allylbromide (0.5 mL), and silver oxide (986 mg, 4.25 mmol) was added thereto, followed by stirring under light shading at room temperature for 12 hours. Silver oxide was separated by filtration, the filtrate was concentrated, and then the residue was purified by silica gel column chromatography (33% ethyl acetate/n-hexane) to obtain the title compound (4.2 mg, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:36](O)=[O:37]>>[CH3:1][O:2][C:3]1[C:4]([CH3:23])=[C:5]([C:14]([O:21][CH3:22])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:6][C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:36]=[O:37]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1c(C)c(Cc2ccccc2O)c(OC)c(OC)c1OC
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Temperature: 80 °C
Yield: 27 %

Procedure:
2-(3,4,5,6-Tetramethoxy-2-methylbenzyl)phenol (8.64 g, 27.17 mmol) and hexamethylenetetramine (5.00 g, 35.67 mmol) were dissolved in trifluoroacetic acid (100 ml) and the solution was stirred under heating at 80° C. for 4 hours. After the completion of reaction, the solvent was removed by distillation and to the obtained residue, water (100 ml) was added. The resulting solution was stirred for 30 minutes and extracted with methylene chloride. The extract was washed with water and then dried, the solvent was removed by distillation and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (2.50 g, 7.23 mmol, 27%).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([OH:20])=[O:19])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:23])=[N-]>ClCCl>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:23])=[O:19])[C:12]2=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccc2n1CCCC2C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1CCCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C

Procedure:
A solution of 269 mg. of 3-benzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylic acid in 10 ml. of dichloromethane is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 3-benzoyl-5,6,7,8-tetrahydropyrrolo[1,2-a]pyridine-8-carboxylate.
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.ClC1N=C(NC2C=CC=C(O)C=2)[C:31](F)=[CH:30][N:29]=1.NC1C=C2C(=CC=1)NC=C2>>[F:18][C:17]1[C:12]([NH:11][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)=[N:13][C:14]([NH:19][C:20]2[CH:21]=[C:22]3[C:23](=[CH:24][CH:25]=2)[NH:29][CH:30]=[CH:31]3)=[N:15][CH:16]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Agent: Nc1ccc2[nH]ccc2c1
Product: Oc1cccc(Nc2nc(Nc3ccc4[nH]ccc4c3)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 5-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-5-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 17.31 min.; purity: 94%; MS (m/e): 366 (MH+).
Reaction SMILES: C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][NH:21]2)=[C:17]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1.[N:31]([C@@H:34]1[C@@H:38]([CH2:39][OH:40])[O:37][C@@H:36](N2C=C(C)C(=O)NC2=O)[CH2:35]1)=[N+:32]=[N-:33]>>[NH2:14][C:15]1[N:23]=[C:22]2[C:18]([N:19]=[CH:20][N:21]2[C@@H:36]2[O:37][C@H:38]([CH2:39][OH:40])[C@@H:34]([N:31]=[N+:32]=[N-:33])[CH2:35]2)=[C:17]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:16]=1
Reactant: Nc1nc(Oc2ccccc2)c2nc[nH]c2n1
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Oc4ccccc4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C
Yield: 54 %

Procedure:
To 800 mL of an aqueous pH 6.0, 50 mm citrate buffer, prepared as described in Example 2c' was added 2-amino-6-phenoxy-9H-purine (0.181 g, 0.8 mmol) and 3'-azido-3'-deoxythymidine (1.069 g, 4.0 mmol). Solution was achieved by heating the mixture at 50° C. with sonication. A sample was removed as a control. A 40 mL solution of trans-N-deoxyribosylase (Example 2b) with an activity of 1500 units/mL was added. The reaction was heated at 50° C. Six days later, 0.181 g, 0.8 mmol, of 2-amino-6-phenoxypurine was added to the reaction. Fifteen days after the reaction was started, another 0.181 g, 0.8 mmol, of 2-amino-6-phenoxypurine and 0.428 g, 1.6 mmol, of 3'-azido-3'-deoxythymidine were added to the reaction. The reaction was stopped after thirty-three days, by heating to 80° C. to precipitate the enzyme, and filtered. The aqueous solution was extracted with ethyl acetate to remove the product. The combined ethyl acetate fractions were dried with magnesium sulfate, filtered and the solvent removed in vacuo to give a foam. The foam was chromatographed on basic alumina grade 1 eluted with chloroform/methanol (99:1, v/v). The fractions containing product were combined and the solvent removed in vacuo to give the product as a foam, 0.48 g, 54% yield.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]1[C:18](O)=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:22]2>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[C:17]([CH3:16])=[C:26]2[C:21]([CH2:22][CH2:23][CH:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:25]2)=[CH:20][CH:19]=1)(=[O:5])=[O:4]
Reactant: Cc1c(O)ccc2c1OC(c1ccccc1)CC2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(OS(=O)(=O)C(F)(F)F)ccc2c1OC(c1ccccc1)CC2
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Step 2 Trifluoromethanesulfonic anhydride (0.613 mL, 3.63 mmol) was added dropwise to a solution of 8-methyl-2-phenylchroman-7-ol (671 mg, 2.79 mmol) in DCM (10 mL) and pyridine (10 mL) at 0° C. After 30 min, the mixture was diluted with EtOAc (70 mL), washed with water (2×30 mL) and brine (30 mL), dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 95:5 to 85:15 hexane-EtOAc) to give 8-methyl-2-phenylchroman-7-yl trifluoromethanesulfonate as colorless liquid (925 mg, 89%). 1H NMR (400 MHz, chloroform-d) δ 7.28-7.61 (5 H, m), 6.97 (1 H, d, J=8.58 Hz), 6.79 (1 H, d, J=8.58 Hz), 5.11 (1 H, dd, J=10.23, 2.31 Hz), 2.99 (1 H, ddd, J=16.73, 11.11, 5.83 Hz), 2.68-2.88 (1 H, m), 2.17-2.32 (4 H, m), 1.88-2.12 (1 H, m). Mass spectrum m/z 390.0 (M+H)+.