Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][Cl:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[ClH:30].[O:19]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Solvent: CCO
Product: Cl
Product: c1ccc(Oc2cccc(CSC3=N[C@@H](c4ccccc4)[C@@H](c4ccccc4)N3)c2)cc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 3-phenoxybenzyl chloride (343 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 350 mg of the product 241. 1H NMR (DMSO-d6) δ 11.25 (s, 2 H), 7.55-7.30 (m, 6 H), 7.30-7.25 (m, 1 H), 7.25-7.10 (m, 1 H), 7.15-6.90 (m, 6H), 6.90-6.70 (m, 4 H), 5.79 (s, 2 H), 4.81 (s, 2 H); MS: m/z 437 (M++1).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.O1CCOCC1>CN(C)C=O>[CH2:15]([N:3]1[C:4]([Br:8])=[C:5]([Br:7])[N:6]=[C:2]1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Brc1nc(Br)n(Cc2ccccc2)c1Br
Temperature: -20 °C
Yield: 90 %

Procedure:
Combine 2,4,5-tribromoimidazole (15.29 g, 0.050 mol), cesium carbonate (18.0 g, 0.055 mol), benzyl bromide (6.3 mL, 0.053 mol) and dimethylformamide (100 mL) and stir at 20° C. for 18 hours. Filter solids and concentrate under reduced pressure. Suspend in dichloromethane, filter through 2 cm pad silica gel and wash with dichloromethane (1 L). Concentrate filtrates under reduced pressure. Redissolve in dichloromethane (15 mL), add 4 M HCl in dioxane (12.5 mL, 0.050 mol), cool to −20° C. and filter solids. Concentrate filtrate, dissolve in ethyl ether, add 1 M HCl/ether (20 mL) and hexane (40 mL), cool −20° C. and filter. Combine solids and dry under reduced pressure to give 19.6 g (90%, 0.045 mol) of the title compound. MS(ES+): m/z=393.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].[CH:12]([CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([O-:17])=[O:16])=O.Cl.[C:25]1(C)C=CC=C[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH:6]/[CH:12]=[C:14](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)\[C:15]([O:17][CH2:25][CH3:26])=[O:16]
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1ccccc1
Reactant: O=CC(C(=O)[O-])c1ccccc1
Agent: Cl
Product: CCOC(=O)/C(=C\Nc1ccc(OC)c(OC)c1)c1ccccc1
Yield: 60 %

Procedure:
A solution of 3,4-dimethoxyaniline (1.50 g, 9.79 mmol) and ethyl ∀-formylphenylacetate (2.07 g, 1.1 eq) in toluene (20 ml ) is refluxed for 18 hours. After cooling, the reaction mixture is diluted with toluene (10 ml) and then acidified with 10% HCl. After extraction, the organic phase obtained is dried over MgSO4 and then evaporated under reduced pressure. The residue is purified by chromatography on a column of silica (eluent: CH2Cl2) to give 1.92 g (60%) of compound 13 in the form of an oil which crystallizes from methanol.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (216 mg, 0.78 mmol)[prepared according to Example 96], N,N-diisopropylethylamine (0.68 ml, 3.90 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (252 mg, 0.78 mmol) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (401 mg, 0.86 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (303 mg, 0.55 mmol, 71% yield) as a clear oil: LCMS (ES) m/e 545, 547 (M, M+2)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([N:11]=[N+:12]=[N-:13])=[N:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:5])C.O1CCCC1.O.[OH-].[Li+]>O.C(OCC)C>[N:11]([C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=[N+:12]=[N-:13]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=Nc1nc(-c2ccc(C(F)(F)F)cc2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
To a mixture of 2.44 g (7.14 mmole) of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester and 45 mL of tetrahydrofuran was added, 3.01 g (71.5 mmole) of lithium hydroxide monohydrate in 33 mL of water. The mixture was stirred at room temperature for 17 hours and then diluted with 300 mL of diethyl ether. The ether layer was extracted three times with 100 mL of water. The combined aqueous phases were acidified by the addition of 1M hydrochloric acid and extracted three times with 100 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 1.76 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[CH:6]=[CH:5]2.C(OCC)(=O)C.[CH3:25][N:26](C)C=O>O.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:25]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7](=[O:18])[CH:6]=[CH:5]2)#[N:26]
Reactant: CCOC(=O)Cn1c(=O)ccc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)ccc2cc(C#N)ccc21
Reaction time: 24 h
Yield: 38 %

Procedure:
Ethyl 2-(6-bromo-2-oxoquinolin-1(2H)-yl)acetate (2.37 g, 7.64 mmol)cuprous cyanide (8.87 g, 99.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (3.50 g, 3.03 mmol) in dimethylforamide (100 ml) was placed into a preheated oil bath at 140° C. After stirring for 24 h, the solution was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was flash chromatographed with 9:1, 4:1, 7:3, and 3:2 methylene chloride:ethyl acetate as the eluant to afford 0.74 g (38% yield) of ethyl 2-(6-cyano-2-oxoquinolin-1(2H)-yl)acetate. Method [7] retention time 2.87 min by HPLC (M+ 257).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[CH2:7][C:8]([S:10][C:5]=2[CH:4]=1)=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:23])[C:18](=[CH:21][CH:22]=1)[CH:19]=O>C(O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]2[CH:19]3[S:10][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=4[CH:7]3[C:8](=[O:9])[O:23][C:17]=2[CH:16]=1
Reactant: COc1ccc2c(c1)SC(=O)C2
Reactant: COc1ccc(C=O)c(O)c1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(=O)C1c3ccc(OC)cc3SC21
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a stirred solution of 6-methoxythianaphthen-2-one (see Docket B-9459) (20 g, 111 mmol) in a mixture of ethanol (100 mL) and methylene chloride (50 mL) was added 4-methoxysalicylaldehyde (17.5 g, 115 mmol) followed by triethylamine (567 mg, 784 mL, 5.6 mmol) at room temperature. After 30 min, a solid began to precipitate and stirring was continued overnight. The mixture was then diluted with cold hexane (1 L) and filtered to yield 28.7 g (82%) of the title product as an off-white solid, pure by 1H-NMR analysis. An analytical sample was obtained by recrystallization from toluene as light yellow crystals, mp 157-165d° C.: 1H-NMR (300 MHz, CDCl3) d 7.33 (d, J=8.6 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.70 (m, 2H), 6.60 (d, J=2.5 Hz, 1H), 5.22 (d, J=7.2 Hz, 1H), 4.33 (d, J=7.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H); IR (CHCl3) 1759 cm-1 ; MS (FD) m/e 314 (M+); Anal. calc'd. for C17H14O4S: C, 64.95; H, 4.50. Found: C, 65.01; H, 4.58.
Reaction SMILES: CO[C:3]1[CH:11]=[CH:10][C:6]([CH2:7][NH:8][OH:9])=[CH:5][CH:4]=1.Br.C1(O)C=CC=CC=1>C(O)(=O)C>[CH2:7]([NH:8][OH:9])[C:6]1[CH:10]=[CH:11][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(CNO)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: ONCc1ccccc1
Reaction time: 5 h
Yield: 33 %

Procedure:
1.28 g (4 mmoles) of N-benzyl-N-mesyl-O-(p-methoxybenzylhydroxylamine prepared as described in Example 1 was treated with 15 ml of a 38% hydrogen bromide solution in acetic acid at room temperature for 20 hours in the presence of 1.5 g of phenol, and the mixture was then concentrated under a reduced pressure. 30 ml of diethyl ether and 10 ml of water and were then added to the resulting residue, and the aqueous layer was separated, concentrated under a reduced pressure to a small volume, adjusted to a pH of 8 with sodium carbonate and allowed to stand for 5 hours in a refrigerator. The crystals precipitated were collected by filtration to obtain 0.15 g (33% yield) of N-benzylhydroxylamine having a melting point of 56°-57° C. (The melting point reported in the literature is 57° C).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[C:5]#[C:6][C:7]1[C:12]([NH2:13])=[C:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:9][N:8]=1)[CH3:2].CC(C)([O-])C.[K+].O>CN1CCCC1=O.O1CCCC1>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[NH:13][C:12]2[C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1)[CH3:23]
Reactant: CCOC(C#Cc1ncnc(Oc2ccccc2)c1N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
4-(3,3-Diethoxyprop-1-yn-1-yl)-6-phenoxypyrimidin-5-amine (2.30 g) was dissolved in 1-methyl-2-pyrrolidone (7.5 mL), and the mixture was cooled to 0° C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 M tetrahydrofuran was added dropwise to this solution, and the mixture was stirred at 0° C. for 30 min. and at room temperature for 1.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→50:50) to give the title compound (1.34 g) as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5](C(NN)=O)[CH:4]=1.FC(F)(F)C(O)=O.C(O[N:25]=O)(C)(C)C.C(O)(C)(C)C>O1CCCC1>[NH3:6].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:25])[CH:4]=1
Reactant: CC(C)(C)ON=O
Reactant: COc1ccnc(C(=O)NN)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COc1ccnc(N)c1
Product: N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 121 %

Procedure:
To a cooled (0° C.) suspension of 4-methoxypyridine-2-carboxylic acid hydrazide (10.0 g, 59.9 mmol) and trifluoroacetic acid (6.83 g, 59.9 mmol) in tetrahydrofuran (120 ml) was added tert-butylnitrite (18.52 g, 179.6 mmol) at such a rate to keep the internal temperature below 5° C. (ca. 45 min). Once addition was complete the mixture was allowed to stir at 0° C. for 30 min and then the solvent was removed in vacuo. Toluene (100 ml) was added and the mixture heated under reflux for 1 h before adding tert-butanol (15 ml, 155.7 mmol). After heating at reflux for a further 10 h the reaction was cooled and the solvent evaporated in vacuo. The residue was suspended in toluene (100 ml), trifluoroacetic acid (5 ml) was added and the mixture heated at reflux for 5 h. The solvent was removed on a rotary evaporator and the residue purified by flash column chromatography on silica eluting with dichloromethane/methanol/conc. ammonia (97:3:0.3) to furnish 4-methoxypyridin-2-ylamine (4.50 g, 61%) as a pale brown solid. 1H NMR (400 MHz, CDCl3) δH 3.90 (3H, s), 6.12 (1H, s), 6.32 (1H, d, J 7), 7.52 (1H, d, J 7), 7.75 (1H, br s).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[N+:8]=1[O-:9].N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>Cl>[N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[N+:8]=1[O-:9])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(N)[n+]1[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cccc(N=[N+]=[N-])[n+]1[O-]
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Methyl 6-aminopyridine-2-carboxylate 1-oxide hydrochloride (Intermediate 122, 3.34 g, 16 mmol) was dissolved in 10% HCl (aqueous) and cooled to 5° C. An aqueous solution of NaNO2 (1.5 g, 21 mmol) was added dropwise maintaining temperature below 5° C. After 15 minutes of stirring, an aqueous solution of NaN3 (1.4 g, 21 mmol) was added dropwise maintaining temperature below 5° C. The reaction was stirred at 5° C. for 30 minutes and slowly warmed to room temperature. The product was extracted with DCM and then the aqueous layer was basified (with 50% NaOH to pH 13) and then extracted again with DCM. Drying (MgSO4) and removal of solvent yielded a yellow oil (2.6 g, 82%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:15])=[N:11][C:12]=2Cl)[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4].C([O-])(=[O:33])C.[Na+]>CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:33])[NH:11][C:10]([Cl:15])=[N:9][C:8]=2[N:7]=[C:6]1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)nc(Cl)c21
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC#CCn1c(N2CCCC(N(C)C(=O)OC(C)(C)C)C2)nc2nc(Cl)[nH]c(=O)c21
Temperature: 120 °C
Reaction time: 7 h
Yield: 75.5 %

Procedure:
A mixture consisting of 580 mg of t-butyl N-[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate, 315 mg of sodium acetate and 6 ml of dimethyl sulfoxide was stirred in an oil bath at 120° C. for 7 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered through a small amount of silica gel. The filtrate was concentrated, and the residue was crystallized with ethyl acetate-hexane to give 420 mg of t-butyl N-[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate. A mixture consisting of an 100 mg aliquot of the compound obtained above, 0.17 ml of methyl iodide, 48 mg of anhydrous potassium carbonate and 0.5 ml of N,N-dimethylformamide was stirred at room temperature for 4 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with water and then with saturated brine. Then, the organic layer was concentrated, and the residue was purified by silica gel column chromatography using 50% ethyl acetate/hexane to give 104 mg of the title compound.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][Br:11])(=[O:8])[O:5]CC)C.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>Br.C(O)C>[C:13]1([NH2:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Br:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CCBr)OCC
Agent: Br
Solvent: Nc1ccccc1
Solvent: CCO
Product: O=P(O)(O)CCBr
Yield: 53.2 %

Procedure:
A solution of about 50 g of diethyl-2-bromoethyl-phosphonate in about 255 ml of about 48% hydrobromic acid was kept at reflux (about 95°-100° C.) overnight. The solvent was removed under reduced pressure and the residue evaporated twice with toluene, giving a syrup. This syrup was dissolved in about 65 ml of about 99% ethanol, about 20 g of aniline was added dropwise and the solid was collected, washed with cold about 99% ethanol (at about 0° C.) and dried in vacuo, giving about 30.6 g of the desired reagent, mp 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]#[CH:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[O:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: Oc1cnc(Cl)cc1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Cl)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Copper (I) iodide (25 mg) and bis-(triphenylphosphin)-palladium(II)-chloride (30 mg) are added to 6-chloro-4-iodo-pyridin-3-ol (200 mg) in N,N-dimethylformamide (3 mL) under an argon atmosphere. Triethylamine (110 μL) is added and the resulting mixture is stirred at room temperature for 1 h. A solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (175 mg) in N,N-dimethylformamide (2 mL) is added dropwise and the reaction mixture is stirred at 55° C. for 3 h. The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30) to give the title compound. LC (method 2): tR=1.40 min; Mass spectrum (ESI+): m/z=337 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][O:4]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C1C=CC=CC=1>[F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8][N:26]=[N+:27]=[N-:28])[CH2:5][O:4]1
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C(F)(F)F)(C(F)(F)F)O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 3.5 h

Procedure:
A sample of 14.00 grams of 2,2-bis(trifluoromethyl)-4-tosyloxymethyl-1,3-dioxolane (m.p. 58°-60° C.) is dissolved in 40 ml of dimethylformamide and 4.85 grams NaN3 is added. The mixture is stirred magnetically at 140°-149° C. for 3.5 hours. The product is diluted with benzene and filtered. The filtrate is washed thoroughly with water, vacuum-stripped and distilled. The product, 2,2-bis(trifluoromethyl)-4-azidomethyl-1,3-dioxolane, has a boiling point of 78° C./20 mm Hg and a refractive index of 1.37447 at 20° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([C:8]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:10]2[N:9]=1)[CH2:5][CH2:6][CH3:7].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH2:4]([C:8]1[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)=[C:11]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:3])=[O:17])=[CH:15][N:10]2[N:9]=1)[CH2:5][CH2:6][CH3:7]
Reactant: C=[N+]=[N-]
Reactant: CCCCc1nn2cc(C(=O)O)ccc2c1Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCc1nn2cc(C(=O)OC)ccc2c1Cc1ccc(Br)cc1

Procedure:
100 ml of a solution of diazomethane in methylene chloride were added at ambient temperature to a suspension of 4 g of the product of Example 11 in 100 ml of methylene chloride and the solvent was eliminated at 40° C. under reduced pressure. Chromatography on silica was carried out (hexane: 80/ethyl acetate: 20) to obtain 3.7 g of the expected product melting at < or=50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][N:8](CC3C=CC(OC)=CC=3)[C:9]2=[O:12])=[CH:5][CH:4]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[Ce].O>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][NH:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Agent: [Ce]
Solvent: O=[N+]([O-])O
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)C(=O)NC2
Yield: 41.8 %

Procedure:
A mixture of 6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (300 mg, 1.1 mmol) and ammonium ceric nitrate (2.2 g, 4.0 mmol) in acetonitrile:water (12 mL, 2:1) was stirred at RT for 1 h. Then the mixture was poured into water and extracted with ethyl acetate. The combined extracts were then washed with sodium hydrogen carbonate and water. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, dichloromethane:MeOH 20:1) to afford the title product (75 mg, 43%) as a light yellow solid. MS m/e=164.2 (M).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([OH:31])=O)=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]([CH3:42])[C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35]>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH:26]([CH3:28])[CH3:27])[C:21]([C:29]([N:39]2[CH2:38][CH2:37][N:36]([C:34](=[O:35])[N:33]([CH3:32])[CH3:42])[CH2:41][CH2:40]2)=[O:31])=[CH:20]3)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Product: CC(C)n1c(C(=O)N2CCN(C(=O)N(C)C)CC2)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21

Procedure:
The title compound was synthesized in analogy to example 47a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid and piperazine carboxylic acid dimethylamide. Off-white solid. MS (m/z): 569.4 (M+H)+.