Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])[CH3:4].[C:13]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[N:23][C:22]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:3]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH:11][S:26]([C:24]1[S:25][C:21]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]=1)(=[O:27])=[O:28])[CH3:4]
Reactant: O=C(c1ccccc1)c1sc(S(=O)(=O)Cl)nc1-c1ccccc1
Reactant: CCOC(=O)CNCCN
Agent: Cl
Product: CCOC(=O)CNCCNS(=O)(=O)c1nc(-c2ccccc2)c(C(=O)c2ccccc2)s1

Procedure:
The title compound was synthesized by the reaction of N-(2-aminoethyl)-glycine ethyl ester 2HCl with 5-benzoyl-4-phenyl-thiazole-2-sulfonyl chloride as per the procedure of example 1. 1H NMR (500 MHz; DMSO-d6) δ 7.46 (d, 2H), 7.36–7.24 (m, 4H), 7.19–7.11 (m, 4H), 4.05 (q, 2H), 3.28 (s, 2H), 3.19 (t, 2H), 2.66 (t, 2H), 1.16 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8]1.I[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.CC(C)C(C1CCCCC1=O)=O>C(OCC)(=O)C.[Cu]I.CN(C)C=O>[S:17]1[CH:18]=[CH:19][C:15]([N:7]2[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8]2)=[CH:16]1
Reactant: Ic1ccsc1
Reactant: OC[C@H]1CCNC1
Agent: [Cu]I
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC[C@H]1CCN(c2ccsc2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.5 %

Procedure:
A dried round bottom flask was charged with copper(I) iodide (0.10 g, 0.53 mmol), cesium carbonate (3.58 g, 11 mmol). The flask was evacuated and backfilled with nitrogen. Under the flow of nitrogen, (S)-pyrrolidin-3-yl-methanol (0.80 g, 7.9 mmol), 3-iodothiophene (0.54 ml, 5.3 mmol), 2-(2-methyl-1-oxopropyl)cyclohexanone (0.35 ml, 2.1 mmol), and N,N-dimethylformamide (5 ml) were added. The mixture was allowed to stir under nitrogen at ambient temperature for 12 hours. The mixture was diluted with ethyl acetate, passed through a glass filter to remove the inorganic salts and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=9/1 to 1/1) to afford (S)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol (0.41 g, 2.2 mmol, 42%) as a brown oil. In the manner as above (2)-(6), with the use of methyl (3R)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate instead of methyl (3S)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate, (R)-[1-(thiophen-3-yl)pyrrolidin-3-yl]methanol was obtained (0.19 g, 1.0 mmol).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Cl:25][C:23]1[CH:22]=[C:21]([C:26]2[N:27]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:29]=[C:30]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:31]=2)[CH:20]=[C:19]([C:12]2[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:14]=4[CH:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:24]=1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Reactant: Clc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)cc(-c2cc3ccccc3c3ccccc23)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
In a stream of argon, 0.52 g (2.36 mmol) of 9-phenanthreneboronic acid, 0.91 g (2.15 mmol) of 2-(3-bromo-5-chlorophenyl)-4,6-diphenyl-1,3,5-triazine and 24.8 mg (0.022 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent comprised of 80 mL of toluene and 10 mL of ethanol, and the temperature of the obtained suspension was elevated to 60° C. 6.45 mL (6.45 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 18 hours. The resultant reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was dissolved in chloroform and the obtained solution was filtered by celite. The filtrate was distilled to remove all volatile materials to give 1.02 g of an intermediate 2-[3-chloro-5-(9-phenanthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as grayish white solid (yield: 91%).
Reaction SMILES: [C:1]([N:5]1[CH2:37][CH2:36][C:35](C)(C)[CH2:34][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:40])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:48])C(=O)C1.O>CN(C=O)C>[C:1]([N:5]1[CH2:37][CH2:36][CH2:35][CH2:34][C:8]2[C:9]([Br:48])=[C:10]3[C:19]4[CH:18]=[C:17]([C@@H:20]5[O:24][C:23]([CH3:26])([CH3:25])[O:22][C@H:21]5[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:16]([O:32][CH3:33])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:40])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c-2cc2c1C(=O)N(C(C)(C)C)CCC(C)(C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1OC(C)(C)O[C@H]1c1cc2c(cc1OC)CCn1c3c(c(Br)c1-2)CCCCN(C(C)(C)C)C3=O
Reaction time: 1 h
Yield: 104.1 %

Procedure:
A solution of 0.95 g of 21d in 10 ml of DMF was treated with 0.32 g of NBS. The reaction was stirred for 1 hr and then poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated and the product filtered through silica gel (using a gradient of heptane-ethylacetate as eluent), to provide 1.08 gr of 21e; LC-MS-ESI: [M+1] 603.13, 605.13. NMR (CDCl3) δ 8.57 and 6.70 (2×s, 2, Ar—H), 5.51 (d, 1, CHO), 4.20 (m, 2, CHO and ethyl ester), 1.25 (t, 3, ethyl ester), 4.32+3.80 (2×m, 2, CH2), 3.78 (3, 3, OCH3), 3.75 (and 3.50 (2×m, 2, CH2), 2.95 and 3.05 (2×m, 2, CH2), 2.65 and 2.70 (2×m, 2, CH2) 1.65-2.0 (bm, 4, 2×CH2) 1.62 and 1.64 (2×s, 6, dimethylketal) 1.57 (s, 9, tertC4H9)
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[C:1]([O:9][C@@H:10]1[CH2:18][C@@H:13]2[O:14][C:15](=[O:17])[CH2:16][C@@H:12]2[C@H:11]1/[CH:19]=[CH:20]/[C@H:21]([C:23]1[S:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[CH:24]=1)[OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C(=O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)c3cc4ccccc4s3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution consisting of (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate (4a, limiting reagent) in 2:1 THF-methanol (0.1 M) cooled to −40° C. is added CeCl3 heptahydrate. The reaction mixture is subsequently cooled to −78° C. and sodium borohydride (2 molar equivalents) is added and the solution is stirred for 1.5 hours. The reaction is quenched by the addition of acetone at −60° C. followed by the addition of a saturated aqueous ammonium chloride solution as the reaction mixture slowly warms to room temperature. The reaction mixture is diluted with brine and acidified with a small amount of 5% aqueous KHSO4. The product is extracted with ethyl acetate twice and the combined organic layers are dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is purified by flash chromatography on regular silica gel eluted with hexanes-ethyl acetate to afford the title intermediate 5a.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([Cl:48])[C:34]=1[OH:49]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (73 mg, 0.253 mmol) to afford the crude product (60 mg) as an off-white solid: ESI MS m/z 572 [C30H35Cl2N3O4+H]+.
Reaction SMILES: ClCCCC(OC(=O)C)CCCCC.BrCC#CC(OC(=O)C)CCCCC.C([O:32][CH:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[C:34]#[C:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])[C:38](=[O:40])[CH3:39])(=O)C>>[OH:32][CH:33]([CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:34]=[CH:35][CH2:36][N:37]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[C:38](=[O:40])[CH3:39]
Reactant: CCCCCC(C#CCN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Agent: CCCCCC(C#CCBr)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCC(O)C=CCN(CCCCCCC(=O)O)C(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 2 except that, in Step B, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-bromo-4-acetoxy-2-nonyne (Example I, Step 3). The product of Step B is ethyl 7-[N-(4-acetoxy-2-nonynyl)acetamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxy-2-nonynyl)acetamido]heptanoic acid (C).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:24]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:25]([CH:28]4[CH2:32][CH2:31][CH2:30][N:29]4[C:33](=[O:43])[CH:34]([NH:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]([CH3:37])[CH3:36])=[N:26][CH:27]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO>[CH3:42][O:41][C:39](=[O:40])[NH:38][CH:34]([C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[C:25]1[N:24]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:50])([CH3:51])[CH3:49])[C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:14]3[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]3)=[CH:18][CH:19]=2)=[CH:27][N:26]=1)=[O:43])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(C(=O)OCc4ccccc4)CC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Solvent: CCO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCNCC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
4-{4-[2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-phenyl}-piperazine-1-carboxylic acid benzyl ester (166 mg, 0.23 mmol) in EtOH (2.5 mL) was treated with 20% PdOH/C (60 mg) and placed under an atmosphere of H2. The reaction was stirred for 18 hours and filtered through a CELITE plug to afford crude (2-methyl-1-{2-[5-(4-piperazin-1-yl-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-propyl)-carbamic acid methyl ester (120 mg), which was used without further purification: MS (ESI) m/z 585 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]OC2C=CC=CC=2)[CH:2]=1.[ClH:15].[CH3:16][OH:17]>O=[Pt]=O>[ClH:15].[CH3:16][O:17][C:3]1[CH:2]=[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CO
Reactant: c1ccc(OCc2cccnc2)cc1
Agent: O=[Pt]=O
Agent: Cl
Product: COc1cccc(C2CCCNC2)c1

Procedure:
To a solution of 3-(3-pyridinyl)methoxybenzene (22.0 g, 0.099 mol) in methanol (250 ml), PtO2 (2 g) and conc. HCl (30 ml) were added and the mixture was hydrogenated at 0.34 MPa in a Parr apparatus. After complete hydrogenation, the catalyst was filtered off. Most of the solvent was evaporated, the residue was made alkaline with 1 M NaOH and extracted with ether. The ether-phase was dried (Na2SO4) and the solvent evaporated giving 18 g of the amine product. The hydrochloride was made and then recrystallized from ethanol/ether yielding 20.9 g (93%), mp. 137°-138.5° C.
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[N:12]=[CH:13]\[CH2:14][CH2:15][C:16]([OH:18])=[O:17])/[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C(O)(=O)C>[O:1]=[C:2]1[N:10]2[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:12][N:11]=[C:9]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2
Reactant: CCCCCn1/c(=N/N=C/CCC(=O)O)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCC(=O)O)nnc12
Yield: 79.5 %

Procedure:
The mixture of (4E)-4-[(2E)-(6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene)hydrazono]butanoic acid (1.367 g, 5.1 mmol) in acetic acid (70 ml) was refluxed for 1 hour. Evaporation of solvent afforded the desired product (1.29 g, 99%) as yellowish solid. LCMS calculated for C14H19N6O3(M+H): 319.2; found: 319.2.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Br)[O:7]1)(=[O:3])[CH3:2].[N:26]1([C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=[N:27]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)[CH:36]=2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Br)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: OB(O)c1cccc(-n2cccn2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(-c4cccc(-n5cccn5)c4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 150 °C
Yield: 52.9 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-Bromo-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl acetate (0.1 g, 0.242 mmol), 3-(1-H-pyrazole-1-yl)phenylboronic acid (0.137 g, 0.726 mmol), potassium phosphate (0.154 g, 0.726 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex dichloromethane (1:1) (0.040 g, 0.048 mmol) were placed in an oven-dried microwave vial and degassed with argon. Anhydrous dioxane (1.5 mL) was added and the reaction was heated to 150° C. for ten minutes in the microwave. The mixture was filtered through a pad of Celite washing with dichloromethane then concentrated. The residue was taken up in dichloromethane and purified on a prep plate using 60% ethyl acetate/hexanes as developing solvent to give the title compound as a yellow solid (0.061 g 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([OH:14])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][OH:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Oc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-1H-pyrazol-3-ol (238 mg, 1.04 mmol; compound prepared in the same way as Example 1, Scheme 1-step 1B), 2-bromoethanol (273 mg, 2.08 mmol), potassium carbonate (0.43 g, 3.12 mmol) and sodium iodide (0.16 g, 1.04 mmol) in dimethylformamide (5 ml) was warmed, under dry nitrogen atmosphere, with stirring, to 60° C. overnight. The solvent was evaporated to dryness in vacuo and residue partitioned between water and ethyl ether. The combined organic phases were washed with water and dried over sodium sulphate, filtered and evaporated in vacuo. The residue was stirred with petroleum ether at 45° C. and decanted for 3 times to yield, after drying, 258 mg of 2-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yloxy)ethanol which was used without further purification in the next step of synthesis
Reaction SMILES: [CH3:1][N:2]1[CH2:10][CH2:9][CH:5]([C:6]([NH2:8])=O)[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:8][CH2:6][CH:5]1[CH2:9][CH2:10][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(CN)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
1-Methylisonipecotamide (6.75 g, 47.5 mmoles) (prepared as described in Preparative Example 245, Step A above) was dissolved in anhydrous THF (350 mL) and the resulting mixture was added in portions to a stirred slurry of lithium aluminum hydride (1.8 g, 47.5 mmoles) in anhydrous THF (100 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min and then heated at 66° C. for 25 h under nitrogen. Distilled water (1.88 mL) was added dropwise to the stirred mixture at 0° C., followed by 20% aqueous sodium hydroxide (1.42 mL) and then distilled water (6.75 mL) and the mixture was stirred for 15 min. The mixture was filtered and the solids were washed with THF and dichloromethane. The combined filtrates were evaporated to dryness and chromatographed on a silica gel column (30×5 cm) using 15%-20% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 4-(aminomethyl)-1-methylpiperidine (0.678 g, 11%): FABMS: m/z 129.1 (MH+); HRFABMS: m/z 129.1389 (MH+). Calcd. for C7H17N2: m/z 129.1392; δH (d6-DMSO): 2.08 ppm (3H, s, —NCH3); δC (d6-DMSO): CH3: under DMSO peaks; CH2: 29.6, 29.6, 46.7, 55.2, 55.2; CH: 46.2.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:40]1([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][N:44]([CH:40]3[CH2:43][CH2:42][CH2:41]3)[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: C1CC(N2CCNCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate (commercially available), 1-cyclobutylpiperazine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (62%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])=[C:4]([C:9]2[C:10]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=3[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:37]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C.O>[F:36][C:30]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=1[O:28][C:3]1[C:2]2[N:1]=[CH:37][NH:8][C:7]=2[CH:6]=[CH:5][C:4]=1[C:9]1[C:10]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[C:11]=2[C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1
Reactant: CCOC([O-])[O-]
Reactant: Cn1cc(-c2ccc(N)c(N)c2Oc2ccc(F)cc2F)c2ccn(COCC[Si](C)(C)C)c2c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3[nH]cnc3c2Oc2ccc(F)cc2F)c2ccn(COCC[Si](C)(C)C)c2c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of 4-[3,4-diamino-2-(2,4-difluorophenoxyl)phenyl]-6-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (460 mg, 0.897 mmol) in tetrahydrofuran (7.76 mL) was treated with ethyl orthoformate (448 μL, 2.69 mmol) followed by addition of p-toluenesulfonic acid monohydrate (17.1 mg, 0.0897 mmol). The resultant reaction mixture was stirred at 50° C. for 1 h, after which time the reaction mixture was diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give the crude product. Purification by gradient flash column chromatography (50% EtOAc/hexanes to 100% EtOAc) gave the desired product (0.378 g, 81%). LCMS calculated for C27H29F2N4O3Si (M+H)+: m/z=523.2. found: 523.2.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Na].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>C(O)C.CCOCC>[CH2:1]([S:13][CH2:15][CH:17]([OH:19])[CH2:18][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: BrCC1CO1
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCCCCCCCCCCCSCC(O)CSCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
26.6 ml Dodecanethiol was added to an ethylate solution of 2.6 g sodium in 100 ml ethanol and the solution was stirred for 1 hour at room temperature. Then 8.5 ml epibromohydrin was added dropwise within 30 min and stirred overnight. The residue was taken up in ether after removing the solvent, washed twice with water and dried. The desired compound crystallized on evaporation of the solution. Yield 28.5 g (62%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:17]1[CH:18]=[CH:19][C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27](O)=[CH:28][CH:29]=2)=[CH:21][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][C:20]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Reactant: Oc1ccc(Cc2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOc1ccc(Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (S)—N-Boc-piperidine-2-ethanol (1.00 g, 4.36 mmol), 4-hydroxydiphenylmethane (0.884 g, 4.79 mmol), and triphenylphosphine (1.26 g, 4.80 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (0.92 ml, 4.80 mmol), and the resulting mixture was stirred at ambient temperature for about 20 h. The clear, yellow solution was concentrated in vacuo. The crude liquid was purified by silica gel flash chromatography to obtain the title compound as a clear, yellow oil (1.20 g, 70%): 1H NMR (400 MHz; CDCl3) δ 7.35 (m, 2H), 7.17 (m, 3H), 7.07 (d, 2H, J=8.8 Hz), 6.79 (d, 2H, J=8.8 Hz), 4.46 (m, 1H), 3.97 (m, 5H), 2.80 (br t, 1H, J=13.2 Hz), 2.12 (m, 1H), 1.85 (m, 1H), 1.60 (m, 5H), 1.40 (m, 10H). MS, m/z 418 (M+Na)+.