Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([N+:26]([O-])=O)=[C:10]([CH:25]=1)[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>[Pd].CO>[NH2:26][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:25][C:10]=1[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cc(F)ccc2[N+](=O)[O-])C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cc(F)ccc2N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Amoniumformiate (1.0 g) was added into a suspension of (R)-tert-butyl 3-(5-fluoro-2-nitrophenoxy)piperidine-1-carboxylate and palladium on charcoal (125.0 mg) in anhydrous MeOH (10.0 ml) at room temperature. The reaction was stirred at room temperature overnight when LCMS analysis indicated consumption of the starting material. The solution was filtered through celite and washed with MeOH. The filtrate was concentrated in vacuo. The residue was triturated with diethylether to remove the ammoniumformiate residues. The solution was filtered and concentrated in vacuo. The residue was purified by chromatography.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 4-methoxybenzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 332.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.42 (br s, 1H); 8.12 (br s, 1H); 7.86 (m, 1H); 7.36 (m, 4H); 6.92 (m, 2H); 6.83 (d, J=5.5 Hz, 1H); 5.76 (br s, 1H); 4.68 (d, J=5.7 Hz, 2H); 3.83 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].[Cl:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:4][C:2]([O:5][C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:18][CH2:17][CH2:16][Cl:15])=[CH:11][CH:12]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 4-hydroxybenzoic acid 1,1-dimethylethyl ester (U.S. Pat. No. 3,625,954) (35.0 g, 0.1804 mol), 3-chlorobromopropane (56.81 g, 0.361 mol), and potassium carbonate (69.1 g, 0.5 mol) was heated 20 h at reflux in 600 mL of acetone. The mixture was cooled to room temperature and filtered. The solvent was removed in vacuo to give an oil. The oil was dissolved in hexanes (400 mL), and the solution was chilled in the freezer. A white solid crystallized and was separated. The solid was dried in vacuo for 6 h at room temperature. This procedure furnished 39.46 g (81%) of a white crystalline solid, mp 57.5°-58.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([OH:20])(=O)[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:13]=[O:14]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:14])[O:20]2)=[CH:2]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: c1ccc2[nH]ccc2c1
Product: O=C1OC(c2c[nH]c3ccccc23)(c2c[nH]c3ccccc23)c2ccccc21

Procedure:
The reaction sequence is further illustrated below under the preferred anhydrous conditions using as specific reactants, indole and phthalaldehydic acid to produce 3,3-di-(indole-3-yl) phthalide. ##SPC7##
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1)=[O:3].[C:12](Cl)(=[O:14])[CH3:13].CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)c(N)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(C(C)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round, bottom flask was added 3-amino-4-fluoroacetophenone (Method 64, 1 g, 6.54 mmol) in DMF (15 ml), followed by the addition of acetyl chloride (0.56 ml, 7.84 mmol) and DIEA (2.3 ml, 13.08 mmol). The solution was set to stir at room temperature. The reaction appeared complete by TLC after 30 min. The reaction was then quenched with water and partitioned with EtOAc. The layers were cut, followed by an additional wash of the aqueous with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue obtained (1.17 g), was used directly in the next step. 1H NMR (CDCl3) δ 8.94 (d, J=7.54 Hz, 1H) 7.71 (d, 1H) 7.43 (s, 1H) 7.15 (s, 1H) 2.56-2.60 (m, 3H) 2.21-2.28 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][N:35]=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>>[O:36]1[C:32]([C:29]2[CH:30]=[CH:31][C:26]([CH2:25][N:15]3[C:14](=[O:17])[N:11]4[N:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[C:9]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:27][CH:28]=2)=[CH:33][CH:34]=[N:35]1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12
Reactant: BrCc1ccc(-c2ccno2)cc1
Product: O=c1n(Cc2ccc(-c3ccno3)cc2)nc2c(-c3ccncc3)c(-c3ccc(F)cc3)cnn12

Procedure:
The title compound was prepared by reacting 7-(4-fluorophenyl)-8-(pyridine-4-yl)-[1,2,4]-triazolo[4,3-b]pyridazin-3(2H)-one, prepared as described in Example 279F, 5-(4-(bromomethyl)phenyl)isoxazole, prepared as described in Example 250A by procedures analogous to those described in Example 2 as a yellow solid (68%). HPLC: 99% at 5.46 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 465 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 5.25 (s, 2H), 6.51 (d, J=0.96 Hz, 1H), 7.01-7.09 (m, 2H), 7.11-7.18 (m, 2H), 7.23 (dd, J1=4.40 Hz, J2=1.76 Hz, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H), 8.21 (s, 1H), 8.28 (d, J=1.76 Hz, 1H), 8.61-8.64 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.[H-].[Na+].[CH3:34]I>C(#N)C.CCOC(C)=O>[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][CH2:6][C@@H:7]1[CH2:9][C@@H:8]1[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][O:23][CH3:34])=[CH:18][N:17]=2)[CH2:14][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(CO)cn3)CC2)c(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)cc3F)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-(4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidin-1-yl)pyrimidin-5-yl)methanol (Step F product, 198 mg, 0.44 mmol) was dissolved in Acetonitrile (6 mL) at room temperature under N2 and sodium hydride (26 mg of a 60% dispersion in oil, 0.66 mmol) was added followed by CH3I (313 mg, 2.2 mmol). The mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, filtered and evaporated in vacuo. The crude material was purified by column chromatography (SNAP, 10 g, 70% EtOAc in hexane) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 2H), 7.78 (dd, 1H), 7.73 (m, 1H), 7.67 (dd, 1H), 4.80-4.64 (m, 4H), 4.28 (s, 2H), 3.71 (dd, 1H), 3.61-3.54 (m, 1H), 3.37 (s, 3H), 3.08 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43-1.22 (m, 3H), 1.15-1.04 (m, 1H), 0.94-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.6 nM.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[C:11]([CH2:12][OH:13])=[C:10]([N:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=[O:20])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][C:23](=[O:25])[CH3:24])[CH:8]=2)[O:3]1
Reactant: CC1(C)Oc2ccc(N)cc2C(n2ccccc2=O)=C1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)C(n1ccccc1=O)=C(CO)C(C)(C)O2
Reaction time: 24 h

Procedure:
A mixture of 1 g of 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-amino-3-chromene, 10 ml of acetic anhydride and 10 ml of pyridine is allowed to stand at 20° C. for 24 hours. The mixture is evaporated, and customary working up gives 2,2-dimethyl-3-hydroxymethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-acetamido-3-chromene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-amino-5-chloropyridine (10.0 g, 0.078 mol) (Aldrich) and triethylamine (12 mL, 0.086 mol) in methylene chloride (200 mL), at 0° C, was added dropwise trimethylacetyl chloride in methylene chloride (15 mL). The reaction was allowed to warm to room temperature while stirring overnight. The resulting mixture was washed with water, brine, and was dried over MgSO4 and filtered. Concentration of the filtrate in vacuo provided a colorless oil (19.2 g). The oil was dissolved in hexanes and cooled causing the precipitation of a solid. The solid was collected by filtration affording the amide as a white solid (14.96 g, 90%): mp 51.4–53.4° C. 1H NMR (CDCl3/300 MHz) 8.25–8.15 (m, 2H), 8.00 (br s, 1H), 7.68–7.60 (m, 1H), 1.28 (s, 9H). Anal. Calc'd for C10H13N2OCl: C, 56.47; H, 6.16; N, 13.17 Found: C, 56.72; H, 6.34; N, 12.88.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15].O>S(=O)(=O)(O)O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc(C(=O)O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5-Acetylsalicylic acid (9.0 g) was dissolved in concentrated sulphuric acid (20 ml). The solution was cooled to 0° C. and treated, with stirring, with a mixture of concentrated nitric acid (density 1.42; 3.8 ml) and concentrated sulphuric acid (3.8 ml), dropwise, at such a rate that the temperature did not exceed 5° C. The mixture was left to stand at 0° C. for 5 hours and then it was poured onto a mixture of ice and water (100 ml). The precipitated solid was filtered off and recrystallized from water to give 5-acetyl-3-nitrosalicylic acid (8.6 g), m.p. 192°-193° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:44])[CH2:20][CH2:21][C:22](=[O:43])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[C:25]([CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])[CH:24]=1)C>C(O)C.C(OCC)(=O)C>[C:38]([CH2:37][CH2:36][C:25]1[CH:24]=[C:23]([C:22](=[O:43])[CH2:21][CH2:20][C:19]([OH:44])=[O:18])[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15])([OH:40])=[O:39]
Reactant: CCOC(=O)CCC(=O)c1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCOc2ccc(C(=O)CCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 57.7 %

Procedure:
Starting with 0.156 g (0.76 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.357 g (0.76 mmol) of 4-[(5-bromopentyl)oxy]-3-(3-ethoxy-3-oxopropyl)-γ-oxobenzenebutanoic acid ethyl ester, the title compound (0.237 g; 63.8% overall yield) was obtained as a white solid, mp 181.5°-184° C. (recrystallized from ethanol-ethyl acetate), using the procedure of example 22.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:5][C:4]=1[CH3:27].[NH3:28]>>[CH3:27][C:4]1[N:5]=[CH:6][N:7]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:3]=1[CH2:2][NH2:28]
Reactant: N
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CCl
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1CN
Yield: 26.4 %

Procedure:
A solution of 5-(chloromethyl)-4-methyl-1-trityl-1H-imidazole (1.00 g, 2.68 mmol) in ammonia (7 N in CH3OH, 4 mL, 28 mmol) was heated to 50° C. in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material purified by column chromatography (silica gel, 100% CH2Cl2 to 50% CH3OH) to provide (4-methyl-1-trityl-1H-imidazol-5-yl)methanamine (250 mg, 26%). 1H NMR consistent.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[N:32][NH:33]3)O1.C([O-])(=O)C.[K+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]([C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:6]=4[N:7]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CC(C)(O)c1cc2nc(Cl)nc(N3CCOCC3)c2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2o1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
2-(2-chloro-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol (60 mg, 1.0 eq) was dissolved in acetonitrile (2.0 ml) and treated with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (123 mg, 2.5 eq), PdCl2(PPh3)2 (14.1 mg, 0.10 eq) and 1M potassium acetate (0.6 ml). The vial was sealed and heated with stirring in the microwave to 140° C. for 30 minutes. The crude reaction mixture was concentrated and purified by reverse phase HPLC to afford 2-(2-(1H-indazol-4-yl)-4-morpholinofuro[3,2-d]pyrimidin-6-yl)propan-2-ol 107. MS (Q1) 380 (M)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.I[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:13](=[O:19])[NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([S:27][CH3:28])[N:22]=2)=[CH:3][CH:4]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CSc1nccc(I)n1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nccc(Oc2ccc(NC(=O)OC(C)(C)C)c3ccccc23)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A mixture of t-butyl (4-hydroxy-1-naphthyl)carbamate (5.0 g, 19.3 mmol), 4-iodo-2-methylthiopyrimidine (4.86 g, 19.3 mmol) and cesium carbonate (7.52 g, 23.1 mmol) in DMF (25 ml) is heated at 70° C. for 20 h. The resulting mixture is diluted with CH2Cl2 (50 ml), washed with water (25 ml×3), dried over Na2SO4 and concentrated. This residue is dissolved in minimum volume of EtOAc at 70° C. and then hexane (20 ml) is added. The resulting solution is left at room temperature overnight, filtered and washed with hexane to obtain t-butyl(4-{[2-(methylthio)pyrimidin-4-yl]oxy}-1-naphthyl)carbamate as a pink solid (4.2 g); Mp: 173-174° C.; 1H NMR (300 MHz, CDCl3) δ 1.56(s, 9H), 2.30(s, 3H), 6.45(d, J=5.7 Hz, 1H), 6.86(s, 1H), 7.27(d, J=8.1 Hz, 1H), 7.47-7.60(m, 2H), 7.87-7.94(m, 3H), 8.32(d, J=5.7 Hz, 1H); MS: 384 (M+1).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[C:28]([O:30][CH3:31])[C:27]4[C:22](=[CH:23][C:24]([O:34][CH3:35])=[C:25]([O:32][CH3:33])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:31][O:30][C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:34][CH3:35])=[C:25]([O:32][CH3:33])[CH:26]=2)[N:21]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:36])=[O:5])=[CH:12][CH:11]=3)[CH2:15][CH2:16]2)[N:29]=1
Reactant: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(OC)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)nc(OC)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 140.3 %

Procedure:
A solution of (14) (0.062 g, 0.13 mmol) in trifluoroacetic acid (3 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a light brown oily residue (0.08 g, quantitative yield); 1H NMR (DMSO) δ 7.68 (d, 2H, J=8.7), 7.25 (s, 1H), 7.23 (s, 1H), 6.66 (d, 2H, J=8.7), 4.54 (d, 2H, J=12.0), 4.15 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.73 (m, 1H), 3.45 (t, 2H, J=12.0), 2.10 (m, 2H), 1.53 (m, 2H): 13C NMR (DMSO) δ 167.5, 156.5, 151.4, 149.7, 148.9, 147.1, 131.2, 117.0, 111.2, 106.1, 103.0, 102.8, 101.1, 56.2, 55.9, 55.3, 47.9, 43.7, 30.9; HRMS (FAB) m/z 439.2001 (M+H)+ (C23H26N4O5 requires 439.1981); Anal. (C23H26N4O5 ·1CF3COOH·1/2H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].[OH2:15]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][OH:15])[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)([O-:3])=[O:2]
Reactant: O
Reactant: C=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(CCO)cc([N+](=O)[O-])c1
Yield: 25 %

Procedure:
3,5-Dinitrostyrene (0.28 g, 1.43 mmol) was dissolved in acetonitrile (150 ml) and water (300 ml) was added. The mixture was poured into a photolysis apparatus and irradiated with an UV-lamp (HPK 125, Phillips) for 3 h. The organic solvent was evaporated and the aqueous phase extracted with methylene chloride (2×100 ml). The solvent was evaporated and the residue was purified by flash chromatography on a column of silica using heptane/ethyl acetate (1/1) as eluent. Evaporation of solvent gave 76 mg (25%) of a crystalline product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].C(N(CC)CC)C.[Br-].[Br-].[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)(Cl)Cl>[C:2]([C:4]1[CH:5]=[C:6]([N:10]=[P:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cccc(N)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1cccc(N=P(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Yield: 70.9 %

Procedure:
A mixture of 67.6 gm of 3-amino acetophenone, 101.2 gm of triethylamine and 100 ml of carbon tetrachloride was added to a stirred suspension of 211 gm of triphenylphosphine dibromide in 1700 ml of carbon tetrachloride. After 20 minutes of refluxing, the mixture was filtered and evaporated to dryness. The residual solid was treated with isopropanol, filtered and dried, yielding 140.2 gm of the title compound, m.p. 135°-136° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][N:7]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[C:6]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc2[nH]cnc12
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc2c1ncn2C1CCCCO1
Temperature: 75 °C
Yield: 92.5 %

Procedure:
6-Bromo-4-methyl-1H-benzo[d]imidazole (1.02 g, 4.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.5 mL, 38.4 mmol) and methanesulfonic acid (0.032 mL, 0.48 mmol) were added and the resulting mixture heated at 75° C. for 49 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50-100% ethyl acetate in hexanes) gave the desired product (1.32 g, 4.47 mmol, 93% yield) as a light yellow solid. MS (ESI) m/z 295.1 [M]+, 297.3 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:11](O)=[O:12].C(Cl)Cl.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[CH3:23][O:22][C:16]1[CH:15]=[C:14]([CH:10]2[C:11](=[O:12])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(C(CSc2ccccc2N)C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C2CSc3ccccc3NC2=O)cc1OC
Yield: 90.6 %

Procedure:
A solution of 9.1 g of the product of Step C, 180 ml of methylene chloride, 6.25 g of 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride and 9 ml of triethylamine was stirred for 90 minutes at ambient temperature and the methylene chloride was evaporated off. The residue was taken up in 90 ml of ethyl acetate and after separation, 7.8 g of the expected product were obtained melting at 174° C. An analytical sample was obtained by crystallization of 200 mg of crude product from 10 ml of ethyl acetate to obtain 120 mg of the desired product melting at 184° C.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH3:30])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH:28]=[O:29])[CH2:26][CH2:25][CH:24]=[CH:23][CH:22]1[CH3:27]>C1(C)C=CC=CC=1>[CH3:30][C:14]1([CH3:13])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH2:28][OH:29])[CH2:26][CH2:25][CH:24]=[CH:23][CH:22]1[CH3:27]
Reactant: CC1C=CCCC1(C=O)C1C2CCC(C2)C1(C)C
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1C=CCCC1(CO)C1C2CCC(C2)C1(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 122.4 %

Procedure:
A 1-L reaction flask equipped with a stirrer, a thermometer, a reflux condenser, a heating mantle, and an addition funnel was charged with Vitride (300 g, 1.32 mol) and toluene (300 g). The resulting mixture was stirred at 20° C. The Diels-Alder product containing 1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-2-methyl-cyclohex-3-enecarbaldehyde (300 g, 0.97 mol, synthesized as above in EXAMPLE VIII) was added over about 2 hours. The temperature was allowed to rise to 43° C. The reaction mass was aged for 3 hours. The excessive Vitride reagent was quenched with ethyl acetate (100 g), followed by sodium hydroxide (25%, 800 g). The temperature was allowed to rise to 50° C. and stirred for another 0.5 hours. The organic phase was washed with hot water (1 L) twice and concentrated to yield the crude product [1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-2-methyl-cyclohex-3-enyl]-methanol (295 g).