Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:32]4[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCO)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.887 min, m/z=450.2; 1H NMR (CDCl3) 1.54 (d, 3H), 2.07-2.29 (m, 2H), 2.34 (m, 3H), 2.97 (m, 1H), 3.55 (m, 1H), 3.74 (m, 1H), 4.06 (d, 3H), 5.64 (m, 1H), 6.93 (m, 1H), 6.95-7.11 (m, 2H), 7.26-7.37 (m, 2H), 7.90 (m, 1H), 8.38 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[C:7]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:6][C:4]=1[OH:5].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([OH:19])(=[O:18])[CH3:17].[C:16]([OH:19])(=[O:18])[CH3:17].[CH3:1][O:2][C:3]1[CH:9]=[C:8]([OH:10])[C:7]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:6][C:4]=1[OH:5]
Reactant: CC(=O)OC(C)=O
Agent: COc1cc(O)c(CC=C(C)C)cc1O
Solvent: c1ccncc1
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methoxy-5-(3-methyl-2-butenyl)hydroquinone (2.35 g) and acetic anhydride (4.6 g) in dry pyridine (20 ml) was stirred for 2 hours at ambient temperature. The mixture was poured into ice water (50 ml) and the separated oil was extracted twice with diethyl ether. The combined extracts were washed twice with diluted hydrochloric acid, dried, and concentrated in vacuo to give a white solid, which was recrystallized from n-hexane to yield 2-methoxy-5-(3-methyl-2-butenyl)hydroquinone diacetate as white crystals (2.89 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 4-benzyloxyphenol (4.2 g) in dimethyl formamide (50 ml) was treated with sodium hydride (840 mg of a 60% dispersion), and the mixture stirred until evolution of gas ceased. There was then added ethyl 3-bromobutyrate (2.9 ml), and the solution stirred overnight. It was then poured into water (300 ml) and the mixture extracted with ether (3×50 ml). The combined extracts were washed with water (3×) and brine, dried (MgSO4) and evaporated to give a crude product as a brown oil (6 g). This was purified by chromatography on silica, eluting with hexane containing increasing amounts of ethyl acetate to give ethyl 3-(4-benzyloxyphenoxy)butyrate as a colourless crystalline solid (4.5 g) NMR (d6DMSO): δ1.25 (3H,t);1.8-2.0 (2H,m); 2.45 (2H,t); 3.9 (2H,t); 4.1 (2H,q); 5.0 (2H,s); 6.8-7.0 (4H,m); 7.4 (5H,m); m/e 314 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[N:6]([C:7]2[S:8][C:9]3[CH2:15][CH2:14][O:13][C:12]4[CH:16]=[C:17]([CH:20]5[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]5)[CH:18]=[CH:19][C:11]=4[C:10]=3[N:33]=2)[C:5](=[O:34])[NH:4][C:3]1=[O:35]>FC(F)(F)C(O)=O.ClCCl>[NH:23]1[CH2:22][CH2:21][CH:20]([C:17]2[CH:18]=[CH:19][C:11]3[C:10]4[N:33]=[C:7]([N:6]5[C:2]([CH3:36])([CH3:1])[C:3](=[O:35])[NH:4][C:5]5=[O:34])[S:8][C:9]=4[CH2:15][CH2:14][O:13][C:12]=3[CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCCc2sc(N4C(=O)NC(=O)C4(C)C)nc2-3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(C3CCNCC3)ccc1-2
Yield: 30 %

Procedure:
tert-Butyl 4-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-8-yl)-tetrahydropyridine-1(2H)-carboxylate was stirred in 50% trifluoroacetic acid in dichloromethane to give 514. Yield 30%. MS (ESI+): 413.2. 1H NMR (500 MHz, DMSO) δ 8.23 (s, 1H), 8.17 (d, J=8.2, 1H), 7.02 (d, J=8.2, 1H), 6.85 (d, J=1.6, 1H), 4.30 (t, J=4.9, 2H), 3.22-3.20 (m, 3H), 2.88 (t, J=11.2, 2H), 2.75 (t, J=12.0, 1H), 1.89 (d, J=12.5, 2H), 1.67 (d, J=12.9, 7H)
Reaction SMILES: CN.[O:3]=[C:4]1[N:10]2[CH2:11][CH2:12][C@H:9]2[C:8]2=[C:13]([C:16]3[O:20][N:19]=[C:18]([CH2:21][N:22]4C(=O)C5C(=CC=CC=5)C4=O)[N:17]=3)[N:14]=[CH:15][N:7]2[C:6]2[CH:33]=[CH:34][S:35][C:5]1=2>C(O)C>[NH2:22][CH2:21][C:18]1[N:17]=[C:16]([C:13]2[N:14]=[CH:15][N:7]3[C:6]4[CH:33]=[CH:34][S:35][C:5]=4[C:4](=[O:3])[N:10]4[CH2:11][CH2:12][C@H:9]4[C:8]=23)[O:20][N:19]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Agent: CN
Solvent: CCO
Product: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)n1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
30 ml of methylamine (33% in ethanol) were added dropwise at 70° to a solution of 2.4 g (5.23 mmol) of (S)-2-[5-(8-oxo-11,11 a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-1-yl)-1,2,4-oxadiazol-3-yl-methyl]-2,3-dihydro-1H-isoindole-1,3-dione in 40 ml ethanol and the mixture was stirred at 70° for a further 2 hours. The reaction mixture was evaporated and the residue was chromatographed (silica gel, methylene chloride/methanol 20:1). There were obtained 1.60 g (93%) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as colourless crystals of m.p. 227° (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[CH2:5]2.[CH3:21][N:22](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[CH3:20][C:12]1([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:21]#[N:22])[CH:3]=3)[C:7]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CN(C)C=O
Reactant: CC1(N2Cc3cc(Br)ccc3C2=O)CCC(=O)NC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1(N2Cc3cc(C#N)ccc3C2=O)CCC(=O)NC1=O
Temperature: 130 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A stirred mixture of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-3-methyl-piperidine-2,6-dione (1.40 g, 4.00 mmol), Zn(CN)2 (0.28 g, 2.40 mmol), Pd2(dba)3 (0.07 g, 0.08 mmol) and dppf (0.09 g, 0.16 mmol) in deoxygenated N,N-dimethylformamide (30 mL) was heated to 130° C. under nitrogen. After 2 h, the solvent was removed in vacuo and the residue was triturated in water (30 mL) then ethyl acetate hexanes (1:1, 30 mL). The product was isolated by filtration, washed with ethyl acetate hexanes (1:1) and dried in vacuo providing 2-(3-methyl-2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1.2 g, 99% yield); 1H NMR (DMSO-d6) δ 1.67 (s, 3H), 1.89-1.95 (m, 1H), 2.55-2.81 (m, 3H), 4.73 (d, J=18.2 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.17 (s, 1H), 10.93 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=3[N:16]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH:33]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH2:33][NH:1][C@@H:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:11][CH2:12][C:13](=[O:17])[NH:14][C:15]=4[N:16]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: N[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ncc(=O)n(CCCN[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.4 %

Procedure:
6-[(4S)-4-Amino-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (94.1 mg, 0.379 mol) and 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (Reference Example 8; 106 mg, 0.456 mmol) were dissolved in chloroform/methanol (10:1, v/v, 6 ml). Molecular sieve 3 A (powder, 1.0 g) was added to the solution and heated under reflux for 3 hours. After cooling, sodium triacetoxyborohydride (145 mg, 0.684 mmol) was added to the reaction mixture and the mixture was stirred overnight at room temperature. After completion of the reaction, the molecular sieve was removed by filtration and a saturated sodium hydrogen carbonate aqueous solution was added to the filtrate and stirred. After separating the organic layer, the aqueous layer was extracted twice with chloroform/methanol (10:1, v/v) and combined with the organic layer. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The obtained residue was purified by thin-layer chromatography (chloroform/methanol) to yield 56 mg (32%) of the title compound in the form of a colorless solid.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:19][CH2:18][C:17]3[CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5]1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:25][CH2:24][NH:23][C:20]([C:15]2[CH:16]=[CH:17][C:18]3[CH2:19][CH:10]([N:7]4[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]4)[CH2:11][CH2:12][C:13]=3[CH:14]=2)=[O:22])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CN1CCN(C2CCc3cc(C(=O)O)ccc3C2)CC1
Reactant: NCCN1CCCC1
Agent: Cl
Product: CN1CCN(C2CCc3cc(C(=O)NCCN4CCCC4)ccc3C2)CC1

Procedure:
6-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide is prepared from 6-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid dihydrochloride and N-(2-aminoethyl)pyrrolidine in a manner substantially analogous to Procedure B (See herein Example 8). Observed mass 371 (M++1).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8]([NH:9][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: COCOc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
4-Methoxymethoxy-2-nitroaniline (7.69 g (38.8 mmol)) was dissolved in 19.0 ml of pyridine. To this, p-toluenesulfonyl chloride (8.14 g (42.7 mmol)) was added with stirring at room temperature and the mixture was stirred at room temperature for 18 hours. Then, water (200.0 ml) was added to the reaction mixture, and the resulting mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with chloroform-ethanol (100:1) as eluent, to give 9.46 g (63%) of 4′-methoxymethoxy-2′-nitro-p-toluenesulfonanilide as a yellow oil.
Reaction SMILES: Cl.O.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][CH2:14][C:15](O)=O)=[CH:11][C:6]=2[CH2:5][CH2:4]1>[Zn].C1(C)C=CC=CC=1>[O:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[C:10]3[C:9](=[CH:8][C:7]1=2)[CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: O=C(O)CCCc1ccc2c(c1)CCO2
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: O
Product: c1c2c(cc3c1CCO3)CCCC2

Procedure:
An amalgam of zinc and mercuric chloride (72 g Zn and 7.1 g HgCL2) is added to a mixture containing 120 ml of concentrated hydrochloric acid, 57 ml of water, 30 g of the compound of Example 1 and 71 ml of toluene, with stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:8])=[O:5].[OH-].[K+].CI.[CH3:26][O:27][CH2:28]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[C:4]([N:6]([CH2:26][O:27][CH3:28])[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:8])=[O:5]
Reactant: COCCl
Reactant: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: COCN(C(=O)Nc1ccc(Cl)cc1)C(=O)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
10.3 g of N-(2,6-dichlorobenzoyl)-N'-(4-chlorophenyl)-urea and 1.88 g of powdered potassium hydroxide (90% are dissolved 40 ml of dimethyl formamide, after which 4.7 of methyl iodide are added drop by drop to the clear solution. The resulting reaction is exothermic. After stirring for two hours the solution is diluted with ice water and the solid substance is isolated. Yield 10.3 g. Melting point 124°-126° C. In a completely similar manner but using methoxymethylchloride instead of methyliodide, N-(2,6-dichlorobenzoyl)-N-(methoxymethyl)-N'-(4-chlorophenyl)-urea is produced. Melting point 121.5°-122.5° C.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][NH:3]1.P(Cl)(Cl)([Cl:15])=O>C(N(CC)CC)C>[Cl:15][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc[nH]c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncnc1Cl
Yield: 86 %

Procedure:
To a mixture of ethyl 3,4-dihydro-4-oxopyrimidine-5-carboxylate (3.54 g) (synthesized according to the method reported by A. R. Todd and F. Bergel on J. Chem. Soc., 364 (1937)) and triethylamine (2.13 g) was added dropwise under ice-cooling phosphorus oxychloride (21 ml), and the mixture was then heated for 1.5 hour under reflux. The reaction mixture was concentrated to dryness, which was poured into ice-water, followed by partitioning between chloroform and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and then dried. The solvent was distilled under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as a pale yellow oil (3.42 g, 86%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[CH:10]2[CH2:13][CH2:14][CH:7]1[CH2:8][CH2:9]2)=[O:5].C([O-])(=O)C.[Na+].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=2)[CH:10]2[CH2:13][CH2:14][CH:7]1[CH2:8][CH2:9]2)=[O:5]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C2CCC(CC2)[C@@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
(2R,3S)-3-Amino-bicyclo[2,2,2]octane-2-carboxylic acid methyl ester hydrochloride (0.34 g, 1.54 mmol) was dissolved in methanol (10 mL). Sodium acetate (0.25 g, 3.08 mmol) was added followed by 4 Å powdered molecular sieves (0.34 g) and 4-fluoro-benzaldehyde (0.16 mL, 1.54 mmol). Sodium cyanoborohydride (0.19 g, 3.08 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, (2R,3S)-3-(4-fluoro-benzylamino)-bicyclo[2,2,2]octane-2-carboxylic acid methyl ester (0.32 g, 1.11 mmol, 72%), as a clear oil. LC-MS (ESI) calcd for C17H22FNO2 291.36. found 292.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH2:22][CH3:23])[NH:17][C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:29])(=O)=O.[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH2:22][CH3:23])[N:17]([CH3:29])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Reactant: COS(=O)(=O)OC
Agent: [Na]
Solvent: CC(C)O
Product: CCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[4-ethyl-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-3-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.34 ppm (d, 1H), 5.75 ppm (s, 1H), 5.25 ppm (m, 1H), 3.45 ppm (s, 3H), 2.61 ppm (m, 2H), 1.36 ppm (d, 6H), 1.31 ppm (t, 3H),
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:19]=1)=[O:4].Cl>C1COCC1.[OH-].[Na+]>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH:19]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)F)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)F)c3)c2c1

Procedure:
Combine N-(2-(5-methoxycarbonyl-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine (200 mg, 0.5 mmol) in 50 mL THF and 1 mL 3 N NaOH. Reflux the mixture overnight, treat with 0.7 mL 5 N HCl and concentrate to dryness. Chromatograph to give the title compound: ISMS 393 (M+1); Analysis for C20H19F3N2O3 CF3COOH 1.2C7H8 2.1H2O: calcd: C, 55.76; H, 5.20; N, 4.28. found: C, 55.51; H, 5.47; N, 4.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)[CH:20]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:27][CH2:26]2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ccn2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)ccn2)CC1
Yield: 30.3 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (211 mg, 0.7 mmol) was reacted with tert-butyl 1-(4-aminopyridin-2-yl)piperidin-4-ylcarbamate (300 mg, 1 mmol) to afford the desired product (120 mg, 30%) as a yellow solid: ESI MS m/z 566 [C28H32BrN5O3+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([O:43][Si](C(C)(C)C)(C)C)[CH3:42])=[CH:36][CH:35]=3)[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:54]([O:53][C:51]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:9]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][CH:20]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][CH:41]([OH:43])[CH3:42])=[CH:38][CH:39]=3)[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=3)=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:52])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(O)Cc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)NCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 35 °C
Reaction time: 17 h
Yield: 25.8 %

Procedure:
To a solution of 77E (172 mg, 0.215 mmol) in 3 mL THF, was added a solution of TBAF (1M in THF, 1 mL, 1 mmol). The mixture was stirred at 35° C. for 17 h, then concentrated. The residue was dissolved in EtOAc, washed with water (2×) and brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (0 to 100% EtOAc/hexanes) afforded 38 mg (26%) of 77F as a yellow glass. MS (ESI) m/z 686.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:14][CH:13]3[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.Cl.[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26]>C(O)(C)C>[C:23]([OH:29])(=[O:28])[CH2:24][C:25]([OH:27])=[O:26].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[N:15]([CH3:16])[CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2CCC1CC(O)(c1ccc(F)cc1)C2
Agent: Cl
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CN1C2C=C(c3ccc(F)cc3)CC1CC2

Procedure:
The title compound was prepared from 3-(4-fluorophenyl)-8-methyl-8-azabicyclo[3.2.1]octan-3-ol (4.7 g, 20 mmol), glacial acetic acid (20 mL) and concentrated hydrochloric acid (20 mL). The free base of the title compound was dissolved in isopropanol and malonic acid (1.7 g, 16.3 mmol) was added, after a while the title compound precipitated as powder and was isolated by filtration. Yield 4.6 g (72%), m.p. 122.2-123° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18].N1C2C(=CC=CC=2)C=CC=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9](/[CH:11]=[CH:12]\[C:13]([CH3:16])([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:6]2[CH2:17][CH3:18]
Reactant: CCn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC(C)(C)O)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CCn1c(-c2cccc(F)c2)nc2c(N)nc(/C=C\C(C)(C)O)nc21

Procedure:
To a solution of 200 mg of 4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-butyn-2-ol in 20 ml of methanol were added 5 μl of quinoline and 20 mg of 10% palladium/barium carbonate and the mixture was stirred in a hydrogen atmosphere at room temperature for 10 minutes. The palladium/barium carbonate was filtered off and the filtrate was concentrated and then the resulting residue was subjected to a silica gel column chromatography (15 g of silica gel; dichloromethane-dichloromethane/methanol=60:1-40:1) to give (Z)-4-[6-amino-9-ethyl-8-(3-fluorophenyl)-9H-2-purinyl]-2-methyl-3-buten-2-ol. This was dissolved in methanol and five drops of 5N hydrochloric acid were added thereto followed by concentrating. Ethyl acetate and ether were added to the resulting residue and the crystals were collected by filtration and washed with ether to give 851 mg of the product. The yield was 26%.