Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:52][OH:53])=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[N:37]=[CH:36][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41]6)[CH2:39]5)=[CH:34][CH:33]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:24]=[C:25]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:51][C:40]6([CH2:43][NH:42][CH2:41]6)[CH2:39]5)=[CH:36][N:37]=4)[C:26](=[O:30])[N:27]([CH3:29])[N:28]=3)[C:18]=1[CH2:52][OH:53])[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CNC4)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 21 h

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (169 mg, 234 μmol) was combined with DCM (10 ml) and TFA (2 ml) to give a yellow solution. The reaction mixture was stirred at 25° C. for 21 h. Conc. in vacuo to afford the title compound as a yellow solid in quantitative yield. (M+H)+=623 m/e.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5](Cl)[N:4]=1)#[N:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+].O>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:11][CH2:12][CH3:13])=[C:5]([O:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)#[N:2]
Reactant: CCNc1nc(C#N)c(C#N)nc1Cl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1nc(C#N)c(C#N)nc1Oc1ccccc1
Yield: 83.7 %

Procedure:
2,3-Dicyano-5-ethylamino-6-chloropyrazine (2.07 g; 0.01 mole) was dissolved in 40 ml of tetrahydrofuran. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.94 g (0.01 mole) of phenol, 0.56 g (0.01 mole) of potassium hydroxide, 5 ml of water and 20 ml of tetrahydrofuran was added dropwise over the period of 10 minutes. Then, the mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the precipitate was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was poured into 80 ml of water. The precipitated crystals were collected by filtration, and recrystallized from benzene to afford 2.22 g (yield 84%) of 2,3-dicyano-5-ethylamino-6-phenoxypyrazine.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(F)c(Br)c1F
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(Br)c1F

Procedure:
A solution of 3-bromo-2,4-difluoroaniline (4.16 g, 20 mmol, EP184384), n-propanesulfonyl chloride (4.6 ml, 40 mmol), pyridine (8 ml), DMAP (97 mg), and DCM (100 ml) was stirred at rt for 16 h. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine. The crude product was purified by silica gel chromatography (8:1 to 3:1 hexanes/ethyl acetate eluant) to give the title compound. MS m/z 313.9 (M+1).
Reaction SMILES: O1C=CC=C1.Cl[C:7]1[N:8]=[C:9]2[CH:19]=[CH:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2.[F-:20]>>[F:20][C:7]1[N:8]=[C:9]2[CH2:19][CH2:18][O:17][C:10]2=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: Clc1nc2ccoc2c2ccccc12
Reactant: [F-]
Solvent: c1ccoc1
Product: Fc1nc2c(c3ccccc13)OCC2

Procedure:
The chloride/fluoride exchange was achieved by the method (reference 3) cited above. Thus 90 mg of 5-chloro-2,3-dihydro-1-oxa-4-aza-cyclopenta[a]naphthalene (Example 217) was suspended in 1.5 mL of Bu4PHF2 and was irradiated under microwave (Smith Reactor) to about 120° C. for 2 hours. After aqueous work up and column purification, 22 mg of fluoride product was obtained (26.9%). LC/MS rt-min (MH+): 1.91 (190) [method B]. The furan derivative (Example 218), 5-chloro-1-oxa-4-aza-cyclopenta[a]naphthalene was sufficiently reactive to be alkylated with the tripeptide directly without fluoride activation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:22]1[CH2:27][CH:26]=[C:25](B2OCC(C)(C)CO2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:25]3[CH2:26][CH2:27][S:22][CH2:23][CH:24]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Reactant: CC1(C)COB(C2=CCSCC2)OC1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(C3=CCSCC3)c2)CC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 67 %

Procedure:
To a mixture of 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 13, step (c), 200 mg, 0.563 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-5,5-dimethyl-[1,3,2]dioxaborinane (as prepared in the previous step, 131 mg, 0.619 mmol) and Pd(PPh3)4 (65 mg, 0.056 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.25 mL, 4.5 mmol). The resulting mixture was stirred at 80° C. for 7 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (15-30% EtOAc/hexane) gave 141 mg (67%) of the title compound as a colorless oil. 1H-NMR (CDCl3; 400 MHz): δ 6.91 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=2.2 Hz), 6.65 (d, 1H, J=8.2 Hz), 5.91 (m, 1H), 4.22 (br s, 2H), 3.66 (br s, 2H), 3.29-3.31 (m, 2H), 2.87 (dd, 2H, J=5.7, 5.7 Hz), 2.77 (m, 2H), 2.47-2.56 (m, 3H), 1.78 (d, 2H, J=12.6 Hz), 1.50-1.63 (m, 2 H), 1.48 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C21H30N2O2S, 375.2 (M+H), found 375.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:16]([C:32](OC)=[O:33])=[N:17][N:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].CCOC(C)=O.O>C1COCC1.CO>[OH:33][CH2:32][C:16]1[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[CH:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[N:17]=1
Reactant: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)cc3)nc2CO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a stirring solution of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazine-3-carboxylate (example 18) (254 mg, 0.5 mmol) in THF/MeOH (1:1) (10 mL) at room temperature under argon was added NaBH4 (95 mg, 2.5 mmol) at 0° C. in an ice bath under argon carefully. The reaction mixture was allowed to warm to room temperature gradually and stirred overnight. EtOAc (20 mL) and water (20 mL) were added to the reaction mixture. Layers were separated. Organic layer were washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 40 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 230 mg (95%) of tert-butyl 4-(3-(hydroxymethyl)-1-(4-(methylsulfonyl)phenyl)-6-oxo-1,6-dihydropyridazin-4-yloxy)piperidine-1-carboxylate was obtained as a white solid MS (ESI) 434 (M+H-tBu).
Reaction SMILES: Cl.[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)[C@@]1(C)CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@]1(C)CCCN1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound (D80) (50 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride (D50) (60 mg) and 4-(Trifluoromethyl)benzyl bromide (0.126 ml). (Na2CO3: 4 eq; reaction time 18 hrs; 68° C.)
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH2:10]([C:13]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][N:14]=1)[CH2:11][CH3:12]>>[N+:6]([C:17]1[C:13]([CH2:10][CH2:11][CH3:12])=[N:14][NH:15][C:16]=1[C:18]([OH:20])=[O:19])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc(C(=O)O)[nH]n1
Agent: O=S(=O)(O)O
Product: CCCc1n[nH]c(C(=O)O)c1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
Fuming sulphuric acid (17.8 ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0 ml), the resulting solution heated to 50° C., then 3-n-propyl-1H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull., 1984, 32, 1568; 16.4 g, 0.106 mol) added portionwise over 30 minutes whilst maintaining the reaction temperature below 60° C. The resulting solution was heated for 18 hours at 60° C., allowed to cool, then poured onto ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4 g), m.p. 170-172° C. Found: C, 42.35; H, 4.56; N, 21.07. C7H9N3O4 requires C, 42.21; H, 4.55; N, 21.10%. 6 (DMSOd6): 0.90 (3H, t), 1.64 (2H, m), 2.83 (2H, m), 14.00 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[S:12][C:13]1[C:14]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[C:15]([O:32][CH3:33])[CH:16]=[CH:17][C:18]=1[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[NH:45]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@H:46]([C:54](O)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[C:60]([O:59][C:57]([NH:45][C@H:46]([C:54]([CH:9]([NH2:8])[C:10]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:11]=1[S:12][C:13]1[C:14]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])=[C:15]([O:32][CH3:33])[CH:16]=[CH:17][C:18]=1[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:58])([CH3:62])([CH3:63])[CH3:61]
Reactant: CCCCCCN1c2ccc(OC)c(CN)c2Sc2c1ccc(OC)c2CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCN1c2ccc(OC)c(CC(=O)OCc3ccccc3)c2Sc2c1ccc(OC)c2C(N)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
72.8 mg of benzyl (6-aminomethyl-3,7-dimethoxy-10-hexylphenothiazin-4-yl)-acetate trifluoroacetate were reacted with 39.7 mg of Boc-Phe-OH analogously to that described in Example 4.7.1. The crystalline benzyl [6-((N-tert.-butoxycarbonyl-L-phenylalanyl)-aminomethyl)-10-hexyl-3,7-dimethoxyphenothiazin-4-yl]-acetate obtained was dissolved in trifluoroacetic acid, whereupon the solution was left to stand at 20° for 10 minutes and concentrated in a vacuum. The residue was dissolved in 3 ml of DMF, whereupon 84.3 mg of Z-Tyr(Bzl)-ONp were added and the pH value was adjusted to 8.5 with DIPEA. After 3 hours the reaction mixture was worked up as described in Example 4.7.1. The crystalline benzyl [6-(((N,O-bis-benzyloxycarbonyl-L-tyrosyl)-L-phenylalanyl)-aminomethyl)-10-hexyl-3,7-dimethoxy-phenothiazin-4-yl]-acetate obtained was further processed analogously to that described in Example 2.2.1., whereby the crude product was crystallized from ethanol. 21.3 mg of 10-hexyl-3,7-dimethoxy-4,6-cyclo-[acetyl-L-tyrosyl-L-phenylalanyl-aminomethyl]phenothiazine were obtained; MS: 723.5 MH+.
Reaction SMILES: [CH:1]1([N:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]([C:15]3[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=3)=[C:13]3[C:8]([C:9]([F:23])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)cc1
Yield: 57.2 %

Procedure:
Prepared according to Method D step C from 2-cyclopentyl-7-fluoro-3-(4-methoxyphenyl)-2H-indazole (0.055 g, 0.177 mmol), boron tribromide (0. 70 mL, 0.74 mmol) and 0.3 mL of cyclohexene to give the product (0.03 g) as an amber solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C(=O)O)c2)CC1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
The mixture of 10 g of 2-nitro-5-chlorobenzoic acid and 30 mL of N-methylpiperazine is stirred at 120° C. for 6 hours. To the reaction mixture 150 mL of ethyl acetate is added. The precipitated yellow crystalline material is filtered off, dissolved in 15 mL of water. The pH of the mixture is adjusted to 6 with acetic acid. The precipitated material is filtered off, washed with water and dried, to obtain 11.2 g of the title compound. m.p.: 212° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[I:12]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]([Br:11])[C:5]2[N:6]([C:8]([I:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Brc1cn2ccnc2c(Br)n1
Solvent: CN(C)C=O
Product: Brc1cn2c(I)cnc2c(Br)n1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 8.7 g (31.4 mmol) 6,8-dibromo-imidazo[1,2-a]pyrazine which was prepared according to a procedure described in the Journal of Medicinal Chemistry, 1984, vol. 27, #2, p. 206-212 in 210 mL N,N-dimethylformamide was added 7.42 g N-iodopyrrolidin-2,5-dione in one portion at 23° C. After 18 hours of stirring at 60° C., the solvent was removed in vaccuo and the residue was taken up in dichloromethane and washed with water and saturated sodium thiosulfate solution. The organic phase was dried over sodium sulphate, filtered and the solvent was evaporated to yield 9.46 g (74.8 of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([CH:21]=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[C-]#N.[K+].[CH3:26][OH:27]>O=[Mn]=O>[Cl:1][C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:19])[CH3:18])[C:10]([CH3:20])=[C:9]([C:21]([O:27][CH3:26])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: CO
Reactant: Cc1nc(Cl)c2c(n1)c(C=O)c(C)n2COCC[Si](C)(C)C
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [K+]
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12

Procedure:
To a well stirred mixture of 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carbaldehyde from example A10 (9.49 g; 27.90 mmol), MeOH (50 mL), KCN (6.00 g; 92.10 mmol) and MnO2 (35.60 g, 383.30 mmol) acetic acid (1.68 g; 27.90 mmol) is added at ambient temperature. After 4 hours the dark mixture is filtered through Celite and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/9:1) affording the title compound as an pale yellow oil.
Reaction SMILES: [K].[CH2:2]([O:4][C:5](=[O:23])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)=[O:8])[CH3:3].[CH:24]1([CH2:30][CH2:31]Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[K+]>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:23])[CH:6]([C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:31][CH2:30][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH3:3]
Reactant: BrCCC1CCCCC1
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCC1CCCCC1)C(=O)c1ccc(OCc2ccccc2)cc1
Yield: 69.4 %

Procedure:
A mixture 100 mg (0.3 mmol) of 3-(4-benzyloxy-phenyl)-3-oxo-propionic acid ethyl ester potassium salt, 86 mg (0.45 mmol) of 2-cyclohexylethyl bromide, and 17 mg (0.1 mmol) of potassium iodide (KI) in 1 mL of dimethylformamide (DMF) in a 4 mL vial was shaken in a sand bath at 80° C. overnight. The mixture was then concentrated to give a residue which was purified via reverse-phase chromatography (Gilson) to afford (after lyophilization) 85 mg (70% yield) of 2-(4-benzyloxy-benzoyl)-4-cyclohexyl-butyric acid ethyl ester as a solid as indicated by LC-MS—calcd for C26H32O2 [M++H]+: 409.23, found: 409.2.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4]Cl.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH2:4][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(C)c(CCl)c1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: Cc1ccc(C)c(Cn2ccc3ccc(CC(=O)O)cc32)c1

Procedure:
The titled compound (26 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 2,5-dimethylbenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=[O:16])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=1[Si:12]([CH3:15])([CH3:14])[CH3:13])[CH3:2].[CH3:19]I>>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4](=[O:16])[C:5]1[C:6]([Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][C:8]([CH3:11])=[CH:9][C:10]=1[CH3:19])[CH3:18]
Reactant: CI
Reactant: CCN(CC)C(=O)c1ccc(C)cc1[Si](C)(C)C
Product: CCN(CC)C(=O)c1c(C)cc(C)cc1[Si](C)(C)C

Procedure:
The title compound was prepared from the compound of Example 58 and MeI (4.0 eq) according to General Method A. Purification by HPLC with 3:17 ethyl acetate/hexanes gave 1.4 g of the title compound as a clear oil, an 83% yield.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34].Cl.[OH-].[Na+]>C(OCC)(=O)C.C(O)C>[CH:17]1([N:7]2[C:6]3[N:22]=[C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])[N:3]=[CH:4][C:5]=3[N:14]([CH3:15])[C:13](=[O:16])[CH:12]3[CH:8]2[CH2:9][CH2:10][CH2:11]3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C2CCCC2N(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C1CCCC1C(=O)N2C
Yield: 34.1 %

Procedure:
A mixture of 0.580 g (0.0018 mole) of (rac)-6-chloro-4-cyclopentyl-9-methyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraazabenzo[f]azulen-10-one (VII-68), 0.372 g (0.0022 mole) of 4-amino-3-methoxybenzoic acid, 36.97 mL of ethanol and 0.468 mL of hydrochloric acid was heated at reflux overnight. Additional ethanol and hydrochloric acid were added and the mixture heated at reflux overnight. The mixture was then cooled, made basic to dissolve solids by the addition of sodium hydroxide solution, transferred to a separatory funnel with ethyl acetate. The aqueous layer was washed twice with ethyl acetate, and then acidified by the addition of 1 M hydrochloric acid. The acidified aqueous layer was extracted twice with ethyl acetate and these extracts were combined, washed successively with water and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.277 g of (rac)-4-(4-cyclopentyl-9-methyl-10-oxo-1,2,3,3a,4,9,10,10a-octahydro-4,5,7,9-tetraaza-benzo[f]azulen-6-ylamino)-3-methoxy-benzoic acid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]>C(OCC)(=O)C.[Pd]>[C:1]([CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.7 %

Procedure:
tert-Butyl 4-(cyanomethylene)piperidine-1-carboxylate (20 g, 91 mmol) was dissolved in ethyl acetate (400 mL), and 10% palladium-activated carbon (3.0 g) was added, followed by stirring at room temperature for 3.5 hours under a hydrogen atmosphere. The reaction solution was filtered with celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.38 (hexane/ethyl acetate=3/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (23 g) as a white solid (quantitative yield).