Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=CC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:13]=1.I([O-])(=O)(=O)=[O:29].[Na+].C(OCC)(=O)C>C(#N)C.CC(C)=O.O.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:29])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(C=Cc3ccccc3)cc2)CO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(C2COC(c3c(F)cccc3F)=N2)cc1
Yield: 97.5 %

Procedure:
At 0° C., 2-(2,6-difluorophenyl-)4-(4-(2-phenylethenyl)phenyl)oxazoline (7.22 g, 20 mmol) and sodium metaperiodate (8.55 g, 20 mmol) were suspended in acetonitrile/acetone/water (1:1:1, 180 ml), and a catalytic amount of ruthenium trichloride hydrate was added. Following extractive work-up with ethyl acetate and column chromatography, 5.6 g of the aldehyde were obtained as a viscous oil.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:4]=[C:5]([S:27]([O-:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([O-:26])(=[O:25])=[O:24].[Na+].[Na+].C(N(C(C)C)CC)(C)C.Br[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49]>CO>[C:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][O:2][C:3]1[CH:4]=[C:5]([S:27]([OH:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([OH:26])(=[O:24])=[O:25])([OH:50])=[O:49]
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Reactant: CCOC(=O)CCCCCBr
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCOc1cc(S(=O)(=O)O)c2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)c4ccc1c2c43
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxypyrene-1,3,6-trisulfonate sodium salt (2.6 g), diisopropylethylamine (2 g) and ethyl 6-bromohexanoate (7 g) in methanol (150 mL) was refluxed for 24 hours. The solvent was removed by rotary evaporation. The product was purified by HPLC. The isolated ethyl ester was redissolved in methanol (100 mL). About 0.5 g NaOH dissolved in 25 mL water was added. The resulting solution was stirred overnight. The methanol was removed by rotary evaporation. To the remaining aqueous solution was added acid until the solution became acidic. The precipitate was collected by filtration and dried under vacuum to give 8-(5-carboxypentoxy)pyrene-1,3,6-trisulfonic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.[Cl-].[In+3].[Cl-].[Cl-].ClC1C=C(Cl)C=CC=1C([C:36]1[C:44]2[C:39](=[C:40]([CH2:46][S:47][CH3:48])[CH:41]=[C:42](F)[CH:43]=2)[NH:38][CH:37]=1)CCO.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:36]2[C:44]3[C:39](=[C:40]([CH2:46][S:47][CH3:48])[CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)=[CH:4][CH:3]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(C(F)(F)F)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 5 h

Procedure:
503 mg (1.86 mmol) of the compound from Example 80A and 75 mg (0.34 mmol) of indium(III) chloride were added to 300 mg (1.69 mmol) of the compound from Example 8 in 15 ml of toluene. The reaction mixture was stirred at 80° C. for 5 h, a further 187 mg (0.85 mmol) of indium(III) chloride were added, and the mixture was again stirred for 5 h. After cooling to RT, the reaction solution was mixed with water and ethyl acetate, and the solid was filtered off. The phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 107 mg (15% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26]CC)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li+].[OH-]>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 70 °C
Yield: 100.4 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 1.868 mmol) in MeOH (9.34 mL) was added LiOH (1 N, 3.74 mL, 3.74 mmol), and the reaction mixture was heated at 70° C. for 15 hours. After cooling, the reaction mixture was concentrated and the resulting residue diluted in water. After acidifying with citric acid, the aqueous layer was extracted with DCM. The combined organics were dried (MgSO4), filtered and concentrated to afforded (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.67 g, 100% yield) as a yellow solid. MS (apci) m/z=357.9 (M+H).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C@H:18]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C:20](=[CH:21][CH2:22][C@@H:23]4[C@@H:39]3[CH2:38][CH2:37][C@@:36]3([CH3:44])[C@H:24]4[CH2:25][CH2:26][C@@H:27]3[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]2)(=O)=O)=CC=1.[I-:46].[Na+]>CC(C)=O>[I:46][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C@H:18]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C:20](=[CH:21][CH2:22][C@@H:23]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:44])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[C@H:28]([CH3:35])[CH2:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:19]1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h

Procedure:
A solution of cholest-5-en-3β-yl 6-(p-toluenesulfonyloxy)hexyl ether (33 g, 51 mmol) and sodium iodide (16 g, 0.106 mol) in acetone (250 ml) was refluxed for 4 hours. The solvent was removed under reduced pressure, filtered, and the collected salts washed well with ether. The filtrate was evaporated and residual yellow oil boiled in hexanes (400 ml). The solution was decanted, concentrated to 200 ml, and stored in the refrigerator for two days. The product was filtered and the mother liquors concentrated to give a total yield of 30 g (97%), m.p. 103.5°-104.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=O)[C:5]2([CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=O)O.[BH4-].[Na+].COC(OC)(O)C.B(F)(F)F.C1CCCCCCC1.NC1C=CC=CC=1>O=[Mn]=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:14][N:16]([CH3:17])[CH3:18]
Reactant: CN(C)C(=O)CC1(O)C(=O)Nc2ccc(Br)cc21
Agent: O=[Mn]=O
Agent: COC(C)(O)OC
Agent: FB(F)F
Solvent: Nc1ccccc1
Solvent: COC(C)(C)C
Solvent: C1CCCCCCC1
Product: CN(C)CCc1c[nH]c2ccc(Br)cc12
Temperature: -15 °C

Procedure:
A 1 L flask is charged with 2-(5-bromo-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide (Reference Example 1) (31.2 g, 0.1 mol), sodium borohydride (11.8 g 96%, 0.3 mol), and 250 mL of dimethoxyethanol (DME). The mixture is cooled to −15° C., and to the stirred suspension, BF3-etherate (56.6 g, 0.4 mol) is added dropwise. The temperature is maintained between −15 and −10° C. during the exothermic addition. The mixture is then allowed to warm slowly to ambient temperature (25-27° C.), and left stirring over night. The mixture is cooled with an ice bath and quenched by the addition of 4N NaOH (200 mL). The formed viscous emulsion is heated to 80° C. for 30 minutes, then diazabicyclo[2.2.2]cyclooctane (DABCO) (12.7 g 97%, 0.11 mol) is added, and then the mixture is heated for two additional hours under reflux. After cooling to ambient temperature, the aqueous layer is removed and the organic layer is extracted twice with each 50 mL of a 4 N NaOH.solution. After re-extraction of the combined inorganic layers with toluene (150 mL), the aqueous phase is disposed off, and the toluene layer is added back into the reaction vessel. To the vessel, additional toluene (150 mL) is added and the mixture is then extracted with water (200 mL). The aqueous layer is separated, and extracted twice with each 150 mL of toluene. After disposal of the inorganic the combined toluene layers are extracted for three times with water (300 mL, 2×150 mL), and the aqueous layer is again discarded. The toluene layer is then extracted twice with 4N HCl (100 mL and 50 mL). Using the combined acidic extracts, the pH is then adjusted to 14 by the addition of 4 N NaOH. Then the aqueous layer is extracted twice with tert-butyl methyl ether TBME (150 mL and 50 mL), and the combined extracts are washed with brine (50 mL) and then transferred into a 500 mL flask. To the stirred TBME solution, MnO2 (34.8 g, 0.4 mol) is then added, and temporarily the temperature rises to 40° C. After one hour the aniline by-product has been converted completely, and then the MnO2 is filtered off. Removal of the solvent from the filtrate gives the title product as a colourless viscous oil which crystallizes (23.85 g, 85%), mp=95-96° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([OH:18])[C:16]([I:17])=[C:12]2[CH:11]=[N:10][N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:27][C:28]1[N:29]([CH3:33])[N:30]=[CH:31][N:32]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]2[N:14]=[C:15]([O:18][CH2:27][C:28]3[N:29]([CH3:33])[N:30]=[CH:31][N:32]=3)[C:16]([I:17])=[C:12]2[CH:11]=[N:10][N:9]=1
Reactant: Cn1ncnc1CCl
Reactant: Oc1nn2c(-c3ccccc3F)nncc2c1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nncc2c1I
Temperature: 25 °C
Reaction time: 25 h
Yield: 81.2 %

Procedure:
To a stirred solution of 7-(2-fluorophenyl)-3-iodopyrazolo[1,5-d][1,2,4]triazin-2-ol (0.4098 g, 1.15 mmol) in anhydrous DMF (16 ml) under nitrogen was added cesium carbonate (1.5009 g, 4.61 mmol), then solid 3-chloromethyl-2-methyl-2H-[1,2,4]triazole hydrochloride (0.2328 g, 1.39 mmol). The mixture was stirred at room temperature for 25 h, then partitioned between water (75 ml) and ethyl acetate (75 ml). The aqueous layer was further extracted with ethyl acetate (2×75 ml), and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 0-5% MeOH/EtOAc) to give 0.4212 g (81%) of the title compound as a white solid: mp=218-219° C. (CH2Cl2-EtOAc); 1H NMR (360 MHz, CDCl3) δ 3.88 (3H, s), 5.52 (2H, s), 7.28 (1H, m), 7.39 (1H, td, J=7.6 and 1.0 Hz), 7.65 (1H, m), 7.76 (1H, m), 7.87 (1H, s), 9.14 (1H;, s); MS (ES+) m/e 452 [MH]+; Anal. Found C, 39.66; H, 2.16; N, 21.34%. C15H11FIN7O requires C, 39.93; H, 2.46; N, 21.73%.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([OH:13])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1.Cl.[CH3:16]O>>[O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:16])=[O:12])[N:5]2[C:4](=[O:14])[NH:3]1
Reactant: O=C(O)C1C=CCn2c(=O)[nH]c(=O)n21
Reactant: CO
Agent: Cl
Product: COC(=O)C1C=CCn2c(=O)[nH]c(=O)n21
Yield: 74 %

Procedure:
In a manner analogous to that described in the first paragraph of Example 17, from 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylic acid and methanolic hydrogen chloride there was obtained in 74% yield methyl 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo-[1,2-a]pyridazine-5-carboxylate of melting point 210°-213° C. (from methanol).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1([CH2:11][C:12](OCC)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.NCC(N)(C)C>C(OCC)(=O)C>[C:5]1([CH2:11][C:12]([NH:3][CH2:2][CH2:1][NH2:4])=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCCN
Reactant: CCOC(=O)Cc1ccccc1
Agent: CC(C)(N)CN
Solvent: CCOC(C)=O
Product: NCCNC(=O)Cc1ccccc1

Procedure:
The procedure of Example IX was repeated in all essential details to produce the above compound, except that equivalent amounts of ethylenediamine and ethyl phenylacetate were substituted for 1,2-diamino-2-methylpropane and ethyl acetate, respectively. The product, which was identified by NMR and IR spectroscopy, had a melting point of 37°-38° C.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: C1CCNCC1
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CCCCC1
Yield: 26.2 %

Procedure:
1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 72A (200 mg, 0.368 mmol) and piperidine (0.109 mL, 1.104 mmol) were reacted as described in Example 73. Isolated yield of 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-ylthio)phenyl)urea (57 mg, 26%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.20 (m, 2H), 4.00 (s, 3H), 2.50-2.25 (m, 6H), 1.95 (m, 2H), 1.60-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Cl>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>[CH:20]([N:17]1[CH2:18][CH2:19][CH:14]([N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:3][C:2]([C:37]4[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=4)=[N:7][C:6]=3[CH:8]=2)[CH3:13])[CH2:15][CH2:16]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CC(C)N1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)N1CCC(N(C)Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 15.8 %

Procedure:
A suspension of (2-chloro-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-ylmethyl)-(1-isopropyl-piperidin-4-yl)-methyl-amine (61 mg, 0.144 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (37 mg, 0.17 mmol), 1M Na2CO3 (0.5 ml, 0.5 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in acetonitrile was heated in a microwave at 140° C. for 25 mins. The reaction was then acidified with 2N HCl (aq) extracted with ethyl acetate, the water layer separated and made basic with K2CO3 (sat. aq) resulting in a precipitate, purified on alumina using 5% methanol in dichloromethane as the eluent to give 419 (11 mg, 16%). NMR (CDCl3, 400 MHz), 1.05 (6H, d, J=6.8), 1.60-1.69 (2H, m), 1.72-1.76 (2H, m), 2.08-2.15 (2H, m), 2.37 (3H, s), 2.48-2.54 (1H, m), 2.71-2.76 (1H, m), 2.95-3.00 (2H, m), 3.89 (4H, t, J=4.4), 3.99 (2H, s), 4.05 (4H, t, J=4.8), 5.2 (2H, s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=483.
Reaction SMILES: CO[CH:3]=[C:4]([C:15]#[N:16])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]([NH2:21])=[NH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:21][C:19]1[N:20]=[C:15]([NH2:16])[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][N:18]=1
Reactant: N=C(N)N
Reactant: COC=C(C#N)CCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(CCCCc2ccccc2)c(N)n1
Yield: 52.5 %

Procedure:
A stirred solution of 2.4 grams (0.011 mole) of 1-methoxy-2- cyano-6-phenyl-1-hexene, 4.2 grams (0.044 mole) of guanidine hydrochloride, and 7.6 grams (0.055 mole) of potassium carbonate in 40 mL of N,N-dimethylformamide was heated at 100° C. to 105° C. for about 20 hours. After this time the reaction mixture was diluted with 100 mL of water. The mixture was then extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with three 75 mL portions of an aqueous 10% lithium chloride solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The residue was subjected to column chromatography on basic alumina that was deactivated to Level III with water. Elution was accomplished with 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.4 grams of 2,4-diamino-5-(4-phenylbutyl)pyrimidine; mp 126°-127° C. The NMR spectrum was consistent with the proposed product.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O.CCOC(C)=O.CCCCCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:12][O:11][C:9]([C:6]1[N:5]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:4]2[CH:3]=[CH:2][O:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)c1cc2occc2[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2occc2n1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1.0 g, 6.06 mmol) in CH2Cl2 (10 ml) was added triethyl amine (1.85 g, 18.2 mmol) and DMAP (148 mg 1.22 mol). Then BOC2O (2.0 g, 9.1 mmol) was added. The resulting mixture was stirred overnight. After the reaction was complete as judged TLC analysis (10% EtOAc/hexane), the reaction mixture was washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the crude product was purified by silica gel chromatography (20% EtOAc in hexane) to give 4-tert-butoxycarbonyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester as a white solid (987 mg, 62%). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.45 (d, J=1.47 Hz, 1H), 6.82 (s, 1H), 6.59 (s, 1H), 3.80 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=C)[CH:5]=[C:6]([I:8])[CH:7]=1.[BH4-].[Na+].C[OH:23].[NH4+].[Cl-]>C(Cl)Cl.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][OH:23])[CH:5]=[C:6]([I:8])[CH:7]=1
Reactant: CO
Reactant: C=C[C@@H](NC(=O)OC(C)(C)C)c1cc(F)cc(I)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CO)c1cc(F)cc(I)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
(R)-tert-butyl (1-(3-fluoro-5-iodophenyl)allyl)carbamate (8.89 g, 23.58 mmol) was dissolved in DCM (236 mL) and cooled to −78° C. Ozone was purged through the mixture until blue color persisted. Reaction mixture was then purged with nitrogen and NaBH4 (8.92 g, 236 mmol) was added in one portion followed by addition of MeOH (120 mL) and the mixture was agitated at same temperature for 2 h and then acetone 20 mL was added. Reaction mixture was agitated for another 1 h and then poured over saturated NH4Cl and then extracted with DCM (500 mL) and then with 3:1 CHCl3/IPA (200 mL) and the organic extracts were combined and dried (magnesium sulfate), and the solvent concentrated in vacuo and the residue purified by flash chromatography to afford 6.74 g (17.7 mmol) of (S)-tert-butyl (1-(3-fluoro-5-iodophenyl)-2-hydroxyethyl)carbamate (75%). LCMS (m/z): 326.1 (MH+-56), 0.90 min.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][NH:21][CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>ClCCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:19]4[C:18]5[CH2:20][N:21]([C:24](=[O:26])[CH3:25])[CH2:22][CH2:23][C:17]=5[NH:16][C:15]=4[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cc(Nc2ccc3c(c2)CCC3)c2c3c([nH]c2n1)CCNC3
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5c(c4)CCC5)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.2 %

Procedure:
Indan-5-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (75 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (102 μL, 0.74 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 64 (21 mg, 25% yield) as an oily residue. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:18])[CH2:9][CH:8]2[CH2:10][CH2:11][CH:5]1[CH:6]=[C:7]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].CCN(CC)CC>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[OH:18][C@@:4]1([CH2:3][CH2:2][O:1][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][C@H:8]2[CH2:10][CH2:11][C@@H:5]1[CH:6]=[C:7]2[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC[C@]2(O)C[C@H]3CC[C@@H]2C=C3c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of 227 mg of rac-(1R*,2R*,4R*)-2-(2-hydroxy-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol, 195 mg of Ts-Cl, 0.16 mL of NEt3 and 11 mg of DMAP in 3 mL toluene was stirred overnight at rt. The reaction mixture was quenched with water, the organic phase was separated, washed with brine and evaporated. The residue was purified by CC with Hept-EtOAc (6:4) to yield 0.32 g of oily rac-toluene-4-sulfonic acid (1R*,2R*,4R*)-2-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl ester as yellowish oil.
Reaction SMILES: [Cu][C:2]#N.C[Mg]Br.[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19](Cl)=[O:20]>C1COCC1>[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19](=[O:20])[CH3:2]
Reactant: COC(=O)c1c(C(=O)Cl)cccc1[N+](=O)[O-]
Reactant: N#C[Cu]
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a suspension of copper(I)cyanide (5.70 g, 63.6 mmol) in 200 mL of anhydrous THF at −78° C. was added methyl magnesium bromide (1.4 M in toluene and THF, 43 mL, 59.3 mmol). The mixture was stirred at −20° C. for 20 min, then cooled to −78° C. A solution of 2-chlorocarbonyl-6-nitro-benzoic acid methyl ester (11.6 g, 47.8 mmol, Step B) in 30 mL of THF was added. The mixture was cooled at −10° C., and slowly warmed to RT, quenched with NH4Cl(aq), and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and purified by flash column chromatography, to provide the titled compound as a white solid.