Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21]C=O)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[CH2:49]1COCC1>CCCCCC.CCOC(C)=O>[Br:1][C:2]1[N:3]([CH2:19][CH2:20][CH2:21]/[CH:49]=[CH:29]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C1CCOC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/CCCn1c(Br)c(Cc2ccc(Cl)cc2)c2ccccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of the product obtained in Step 4 in 8 mL of THF was added 0.3 g (carbethoxymethylene)triphenylphosphorane. The reaction mixture was stirred for 2 hours at 50° C. and diluted with 20 mL of 10:1 hexane/EtOAc. The mixture was then filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluted with 9:1 hexane/EtOAc to give 0.2 g of the title compound as an oil.
Reaction SMILES: C1(=O)[N:5]([CH:6]2[CH2:11][S:10][C@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[C:7]2=[O:28])C(=O)C2=CC=CC=C12.C(Cl)(Cl)Cl.CNN>CCOCC>[NH2:5][CH:6]1[CH2:11][S:10][C@H:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]([CH2:18][C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])=[O:20])[C:7]1=[O:28]
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CS[C@@H]1c1ccccc1
Agent: CNN
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the trimethylsilyl ester product from part (b) (1.17 g., 2.36 mmole) in 4 ml. of dry chloroform is treated with N-methylhydrazine (217 mg., 4.72 mmole). The stoppered reaction is stirred at room temperature overnight, then diluted with ether and filtered to remove N-methyl-phthalhydrazide. Removal of organic solvents in vacuo yields (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, 2-(trimethylsilyl)ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:31]=2[CH3:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:32][C:31]=2[CH3:38])[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(C=O)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-2′,4-dimethyl-[1,1′-biphenyl]-3-carboxamide (410 mg, 0.79 mmol) and morpholine (210 mg, 2.38 mmol) in dichloroethane (10 mL), acetic acid (280 mg, 4.77 mmol) was added and reaction stirred at room temperature for 30 minutes. Then sodium triacetoxyborohydride (580 mg, 2.71 mmol) was added to the reaction mixture at 0° C., allowed to attain room temperature and stirring continued for overnight. On completion, reaction mixture was diluted with dichloromethane, washed with water, saturated aqueous sodium bicarbonate solution and dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (125 mg, 26.76%).
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>CN(C=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccoc1=O
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (10.0 g, 65 mmol, Aldrich) in DMF (80 mL) at ice bath temperature was added a solid of 4-fluoroaniline (7.21 g, 65 mmol), stirred for 15 min. and the reaction mixture was warmed to rt, stirred for 3 h at rt. To the 4-fluoroaniline adduct intermediate formed via Michael addition was added in situ solids of EDCI.HCl (14.8 g, 77 mmol) and DMAP (1.80 g) at rt. The reaction mixture was stirred at rt overnight. Most of DMF was removed in vacuo, and to the residue were added 1N aq HCl (150 mL) and EtOAc (400 mL), the EtOAc layer was separated, and the aqueous layer was washed with EtOAc (2×200 mL), the combined EtOAc layer was washed with brine (150 mL), dried over MgSO4 and concentrated in vacuo. The residue was triturated with iPrOH (180 mL) to obtain the 1st crop of product (8.5 g) as a yellow solid. The mother liquor was concentrated, and the residue was triturated with a small amount of ether to obtain the 2nd crop of product (2.5 g, total 11 g, 68%). 1H NMR (CDCl3) δ 8.23 (dd, 1H, J=7.2, 2.2 Hz), 7.57 (dd, 1H, J=6.6, 1.7 Hz), 7.32-7.34 (m, 2H), 7.17 (t, 2H, J=8.8 Hz), 6.32 (t, 1H, J=7.1 Hz), 3.89 (s, 3H); MS(ESI+) m/z 248.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[CH:39]=[CH:38][C:35]([NH:36][CH3:37])=[C:34]([N+:40]([O-:42])=[O:41])[C:33]=1[O:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH:45]1([CH2:44][O:43][C:33]2[C:34]([N+:40]([O-:42])=[O:41])=[C:35]([NH:36][CH3:37])[CH:38]=[CH:39][C:32]=2[C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: CNc1ccc(Br)c(OCC2CCCCC2)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(OCC2CCCCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and 4-bromo-3-(cyclohexylmethoxy)-N-methyl-2-nitroaniline as the starting materials. LCMS calculated for C29H33N4O6S (M+H)+: m/z=565.2. found: 565.1.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:36])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>>[ClH:45].[CH:31]([N:27]1[C:26]([C:20]2[S:21][C:22]3[CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([C:11]5([OH:36])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:35]=[CH:34][C:17]=4[C:18]=3[N:19]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(O)CCNCC3)ccc1-2
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 4-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 39 μmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 3 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (Si—NH2, gradient 1-4% MeOH in DCM). The purified product was dissolved in MeOH (5 mL) and HCl (0.5 mL, 3N in MeOH) added. The reaction mixture was concentrated in vacuo and the residue triturated with MeCN to give 517 as a colourless solid (9 mg, 51%). LCMS: RT=2.94 min, [M+H]+=412 [ad823591] 1H NMR 400 MHz (d6-DMSO) δ: 8.38 (1H, d, J=8.2 Hz), 7.97 (1H, s), 7.28 (1H, dd, J=8.2, 1.9 Hz), 7.20 (1H, d, J=1.9 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t, J=5.0 Hz), 3.49-3.29 (6H, m), 2.29-2.17 (2H, m), 1.98-1.90 (2H, m), 1.59 (6H, d, J=6.6 Hz)
Reaction SMILES: [C:1]1([C@@H:7]2[C@@H:16]3[CH2:17][CH2:18][NH:19][C@@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[C:35](O)=[O:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[C:1]1([C@H:7]2[C@H:16]3[CH2:17][CH2:18][N:19]([C:35]([C@H:30]4[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]4[NH:28][C:20](=[O:27])[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:36])[C@H:15]3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc([C@H]2Nc3ccccc3[C@H]3NCC[C@@H]23)cc1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Agent: CCOC(=O)OC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CCCC[C@@H]1C(=O)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21)c1ccccc1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
To a mixture of (3aR*,4S*,9bS*)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (620 mg, 2.47 mmol), (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (671 mg, 2.7 mmol), triethylamine (0.72 ml, 5.2 mmol), acetonitrile (17 ml) and tetrahydrofuran (17 ml) was added dropwise DEPC (440 mg, 2.7 mmol) under ice-cooling, and the mixture was stirred for 10 min. The mixture was allowed to return to room temperature and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried (over anhydrous Na2 SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (30 g), and eluted with hexane-ethyl acetate (9:1-7:3, v/v) to give the title compound (735 mg, 62%) as an amorphous form.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:19]=2)[NH:14][C:13]=1[C:28]([OH:30])=[O:29])=O)(C)(C)C.[ClH:31].C(OCC)C>C(Cl)Cl.O1CCOCC1>[ClH:31].[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:19]=2)[NH:14][C:13]=1[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)NCCCc1c(C(=O)O)[nH]c2ccc(-c3ccccc3F)cc12
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCCc1c(C(=O)O)[nH]c2ccc(-c3ccccc3F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the above carboxylic acid (13 mg, 0.031 mmol, 1.0 equiv) in methylene chloride (2 mL) at 0° C. was added 0.2 mL of 4 N HCl in dioxane. The reaction was stirred at ambient temperature for 1 h. Then 10 mL of diethyl ether was added to the reaction and the reaction concentrated. To this residue was added 5 mL diethyl ether and the solid was filtered off and washed with diethyl ether several times and air dried for 15 min to provide the title compound (8 mg); MS, electrospray, 313 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.C(N(CC)C1C=CN=CC=1)C.[CH2:29]([O:31][P:32]([CH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)([O:34][CH2:35][CH3:36])=[O:33])[CH3:30]>ClCCl.O>[CH2:35]([O:34][P:32]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:42]([NH:1][C:2]2[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=2[C:4]#[N:5])=[O:43])=[CH:45][CH:46]=1)([O:31][CH2:29][CH3:30])=[O:33])[CH3:36]
Reactant: CCOP(=O)(Cc1ccc(C(=O)Cl)cc1)OCC
Reactant: N#Cc1cc(Br)ccc1N
Agent: CCN(CC)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2ccc(Br)cc2C#N)cc1)OCC
Reaction time: 10 h

Procedure:
3.94 Grams (20 mM) of 2-amino-5-bromobenzonitrile, 2.22 g (22 mM) of triethylamine and 0.49 g (4 mM) of 4-diethylaminopyridine were dissolved in 40 ml of anhydrous dichloromethane. To this solution was added dropwise 40 ml of anhydrous dichloromethane solution with 5.81 g (20 mM) of 4-diethoxyphosphinoylmethylbenzoyl chloride at 0° C. with stirring. After the stirring was continued for 10 hours at room temperature, 50 ml of water was added to the reaction mixture, and the whole mixture was extracted with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate and concentrated. Thus obtained residue was purified by means of a silica gel column chromatography (eluted with chloroform:ethyl acetate=1:2). The crude crystals were recrystallized from benzene-n-hexane to yield 2.94 g of 4-diethoxyphosphinoylmethyl-N-(4-bromo-2-cyanophenyl)benzamide as colorless crystals.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[N:18]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[C:17](=[O:33])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.BrC[C:43]1[CH:52]=[CH:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=1>C(Cl)Cl.C(OCC)(=O)C>[Cl:25][C:22]1[CH:21]=[C:20]2[C:19](=[CH:24][CH:23]=1)[N:18]([CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[C:17](=[O:33])[CH:16]=[C:15]2[NH:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH2:13][CH2:12]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(=O)n(Cc3ccncc3)c3ccc(Cl)cc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1cc(NC2CCN(Cc3ccc4ccccc4c3)CC2)c2cc(Cl)ccc2n1Cc1ccncc1
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
4-(6-Chloro-2-oxo-1-pyridin-4-ylmethyl-1,2-dihydroquinolin-4-ylamino)-piperidine-1-carboxylic acid t-butyl ester (0.58 g, 1.2 mmol) was dissolved in DCM (10 mL) and treated with trifluoroacetic acid (5 mL). The solution was stirred for 15 minutes before evaporating under reduced pressure. The crude amine was dissolved in acetonitrile (25 mL) prior to addition of sodium carbonate (1.22 g) and a drop of triethylamine. The mixture was stirred for 5 minutes before addition of 2-(bromomethyl)naphthalene (0.31 g, 1.4 mmol). After 2 hours the reaction was found to be complete by TLC analysis and the mixture was diluted with ethyl acetate, washed with 1N NaOH, and dried with sodium sulfate. Evaporation under reduced pressure gave the crude product which was purified by silica chromatography using DCM and methanol eluent to give the title compound (0.42 g). 1H NMR (300 MHz, CDCl3) δ ppm 2.04 (2H, m), 2.22 (2H, m), 2.67 (2H, m), 3.23 (2H, m), 3.67 (1H, m), 4.02 (2H, s), 5.20 (1H, m), 5.47 (2H, m), 5.82 (1H, s), 6.93 (1H, d, J=8.96 Hz), 7.05 (2H, m), 7.32 (1H, m), 7.46-7.52 (2H, m), 7.65 (1H, m), 7.72 (1H, m), 7.84 (3H, m), 7.91 (1H, m), 8.48 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([N:11]=[N+]=[N-])[N:3]=1.Cl>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1
Reactant: [N-]=[N+]=Nc1nc(N)nc2nc[nH]c12
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1nc(N)c2[nH]cnc2n1
Yield: 46.9 %

Procedure:
9-(R)-2-phosphonomethoxypropyl)-2-amino-6-azidopurine (0.30 g, prepared according to Example 27) in 50% aqueous methanol (200 ml) containing hydrochloric acid (0.5 ml) was hydrogenated over 10% Pd/C (0.5 g) overnight at room temperature. The mixture was filtered, washed with water, filtrate alkalized with ammonia and evaporated in vacuo. The residue was deionized on a column of Dowex 50 X 8 (50 ml) (cf. Example 25) and the ammonia eluate evaporated to dryness. The residue in water (pH adjusted to 9) was applied on a column of Dowex 1 X 2 (acetate) which was first washed with water to remove salts and the product was then eluted with 1 M acetic acid. The fractions containing product were pooled, evaporated to dryness and codistilled with water (3×20 ml). The residue was crystallized from water (ethanol added to turbidity) to afford 9-(R)-2-phosphonomethoxypropyl)-2,6-diaminopurine (120 mg) identical with the preparation according to Example 19.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[CH2:8][C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2].[Li][CH2:28]CCC.CCCCCC.CI>C1COCC1>[CH2:1]([CH:3]([N:6]1[C:14]2[CH:13]=[C:12]([CH3:15])[N:11]=[C:10]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[CH3:25])[C:9]=2[CH:8]([CH3:28])[C:7]1=[O:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1C(=O)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Solvent: CCCCCC
Product: CCC(CC)N1C(=O)C(C)c2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a −78° C. solution of 1-(1-ethyl-propyl)-6-methyl-4-(2,4,6-trimethyl-phenoxy)-1,3-dihydro-pyrrolo[3,2-c]pyridin-2-one (352 mg, 1.0 mmol) in 2 ml of dry THF was added 2.5M BuLi in hexane (0.4 mmol, 1.0 mmol). The resulting mixture was stirred at −78° C. for 30 min, then transferred to a −78° C. solution of methyl iodide (3 ml) in 3 ml of dry THF. The resulting mixture was stirred at −78° C. for 1 hour, quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic layer was dried and concentrated to give a clear oil which was purified through silica gel column chromatography using hexane to 10% ethyl acetate in hexane as eluent to give the title compound as tan solid 214 mg (68%). 1H NMR (CDCl3) δ 6.88 (s,2H), 6.47(s,1H), 4.1(m,1H), 3.56(q,1H), 2.30(s,3H), 2.26(s,3H), 2.07(s,6H), 1.7–2.0(m,4H), 1.60(d,3H), 0.86(t,6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:29]=[CH:28][C:27](Br)=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:31](B1OC(C)(C)C(C)(C)O1)=[CH2:32].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[N:29]=[CH:28][C:27]([CH:31]=[CH2:32])=[CH:26][C:3]=1[C:4]([C:6]1[N:11]=[C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:14][CH2:13]2)[CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(N2CCCN(C(=O)CC(F)(F)F)CC2)n1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1cnc(N)c(C(=O)c2cccc(N3CCCN(C(=O)CC(F)(F)F)CC3)n2)c1
Yield: 21.5 %

Procedure:
A mixture of 1-(4-(6-(2-amino-5-bromonicotinoyl)pyridin-2-yl)-1,4-diazepan-1-yl)-3,3,3-trifluoropropan-1-one (355 mg, 0.73 mmol), vinyl boronic acid pinacol ester (0.15 ml, 0.88 mmol), tetrakis(triphenylphosphine)palladium(0) (42 mg) and a 2M aqueous solution of sodium carbonate (2 ml) in ethanol (1 ml) and toluene (3 ml) was heated under microwave irradiation at 110° C. for 5 hours. The reaction mixture was concentrated in vacuo. The residue was slurried in ethyl acetate, filtered to remove the inorganic salts and concentrated to dryness in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an orange solid (68 mg, 21% yield).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[CH:2]=[CH2:3].[C:14]([Li])([CH3:17])([CH3:16])[CH3:15].[Bi](Cl)(Cl)Cl.C(=O)=O.[BiH3:26]>C(OCC)C.C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Bi:26]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=[CH:6]4)[C:6]3[CH:15]=[C:14]4[C:17](=[CH:8][CH:7]=3)[N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=[CH:16]4)=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)[CH:2]=[CH2:3]
Reactant: [Li]C(C)(C)C
Reactant: [BiH3]
Reactant: C=CCn1ccc2cc(Br)ccc21
Agent: Cl[Bi](Cl)Cl
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCn1ccc2cc([Bi](c3ccc4c(ccn4CC=C)c3)c3ccc4c(ccn4CC=C)c3)ccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-allyl-5-bromoindole (730 mg., 3.09 mmol., 1 eq.) in diethyl ether (15 mL) at -78° C. under N2 was added t-butyllithium (1.8 mL., 3.09 mmol., 1 eq., 1.7M solution in pentane). The mixture was stirred at -78° C. under N2 for 1 h. To this mixture was added a solution of bismuth trichloride (292 mg., 0.93 mmol., 0.3 eq.) in dry THF (3 mL.) dropwise via syringe. The ice bath was packed with dry ice and the flask covered. The mixture was allowed to warm slowly to room temperature overnight. The reaction mixture was then diluted with toluene and washed with brine. The layers were separated and the aqueous layer extracted 3×with toluene. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in ether and filtered through a 0.4 micron pTFE membrane. The product started to crystallize. Cooled solution in freezer. Collected crystals giving 200 mg. of tris-1-allylindol-5-yl)bismuthine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:21]([N:20]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:4][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:25])[CH2:23][CH3:24])[CH3:22]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CNS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To a solution of {5-[3-(4-aminomethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (60 mg, 168 μmol) and DIPEA (33 mg, 252 μmol) in DCM (10 mL), methanesulfonyl chloride (23 mg, 202 μmol) is added. The mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM, the organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined and concentrated. The product is dissolved in methanol and filtered over Amberlyst A21. The filtrate is evaporated and dried to give the title compound (10 mg) as a colourless resin; LC-MS: tR=0.52 min; [M+1]+=435.03; 1H NMR (CDCl3): δ1.14 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 2.68 (q, J=6.8 Hz, 4H), 2.93 (s, 3H), 3.79 (s, 2H), 4.42 (d, J=5.8 Hz, 2H), 5.04-5.10 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.68 (s, 1H), 8.15 (d, J=8.3 Hz, 2H).