Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7](=[CH:8][CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2].B.CSC.[OH2:36].[Na]>C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([C@@H:8]([OH:36])[CH2:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:13][CH2:12]4)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CCC3=C2CC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]32)C1
Reactant: O
Agent: B
Agent: [Na]
Solvent: CSC
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C[C@H](O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Temperature: 0 °C

Procedure:
Cholesta-5,8-diene-3β-yl acetate (1.0 g) is dissolved in 250 ml diethylether. The reaction mixture is cooled to 0° C. and 2.35 ml of borane-dimethylsulphide-complex (2 M solution in tetrahydrofuran) is added. The reaction mixture is warmed to room temperature within 2 hours. Then, 26 ml water, 26 ml sodium hydroxyde solution (10% aqueous) and 3.65 ml hydrogen-peroxyde (30%) are added at 0° C. After aqueous work-up and column chromatography 3β-(acetyloxy)-5α-cholest-8-ene-6α-ol (140 mg) is isolated.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([F:26])[CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: OB(O)c1cncc(F)c1
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3cncc(F)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 5-fluoropyridine-3-boronic acid using a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.84 min, m/z=417 (M+1); 1H NMR (CDCl3) 8.58 (s, 1H), 8.45 (d, 1H, J=3 Hz), 7.57-7.54 (m, 1H), 7.39-7.30 (m, 5H), 7.27-7.25 (m, 2H), 6.93 (d, 2H, J=8 Hz), 5.80-5.68 (m, 2H), 5.11-5.03 (m, 2H), 2.97-2.91 (m, 1H), 2.69-2.55 (m, 2H), 2.41-2.21 (m, 3H), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:4][CH2:7][C:6]([C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])=[O:8]
Reactant: CC(=O)c1ccccc1N(C)C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CN(C=O)c1ccccc1C(=O)CCl
Reaction time: 2 h

Procedure:
A solution of sulphuryl chloride (119 ml) in dichloromethane (168 ml) was added dropwise to the o solution of 2'-acetyl-N-methylformanilide at 0° under a nitrogen atmosphere. The mixture was stirred for 2 hours at 0° and then cold (5°) water (488 ml) was added dropwise over a period of 1 hour. The dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 2'-(2-chloroacetyl)-N-methylformanilide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:20]([F:23])([F:22])[F:21])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>O1CCOCC1.CCOCC>[ClH:24].[CH3:19][C:17]1[N:18]=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15][C:16]=1[C:20]([F:23])([F:21])[F:22]
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of 1.45 mmol 4-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dioxane was added dropwise 21.8 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 2 h. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a white crystalline solid (yield 68%). MS (m/e): 252.3 (M+H+, 100%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1.O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[Cl:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl)C(C)C
Reaction time: 0.75 h

Procedure:
To a suspension of potassium carbonate (0.892 g, 6.46 mmol, 1.10 equiv.) and 2-amino-3,5-dichloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (2.05 g, 5.87 mmol) in toluene (30 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)-pyrazole-3-carbonyl chloride (2.02 g, 5.87 mmol, 1.00 equiv.) in toluene (20 mL) at 60° C. After 45 min at this temperature, the mixture was cooled and water was added.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([F:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:3]1[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][CH:10]=[C:9]([F:12])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(F)ccc(N)c1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(F)ccc(NS(C)(=O)=O)c1F
Reaction time: 24 h

Procedure:
To a solution of methyl 3-amino-2,6-difluorobenzoate (530 mg, 2.83 mmol) and pyridine (0.28 mL, 3.40 mmol) in 10 mL CH2Cl2 was added methanesulfonyl chloride (0.24 mL, 3.11 mmol). After 24 h at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CHCl3 to provide crude methyl 2,6-difluoro-3-[(methylsulfonyl)amino]benzoate as a solid (ESI-MS 264 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2,6-difluoro-3-[(methylsulfonyl)amino]benzoic acid (ESI-MS 250 (M−H)), which was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=[CH:3]1.[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=4)[N:4]=[CH:3]3)=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2ccc(Cl)cc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccc(Cl)cc2c1=O

Procedure:
3-Amino-6-chloro-4(3H)-quinazolinone and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.70 (m, 12H), 1.93-1.98 (m, 3H), 2.10 (s, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 11.18 (s, 1H) ppm; MS (DCI/NH3) m/z 372 (M+H)+; Elemental Analysis: Calculated for C20H22ClN3O2.0.2H2O: C, 63.98; H, 6.01; N, 11.19. Found: C, 3.87; H, 5.85; N, 11.14.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[F:28])[NH:24][N:23]=[CH:22]3)=[O:17])=[CH:4][C:3]=1[N+:29]([O-])=O.Cl[Sn]Cl.O.[OH-].[Na+]>CCOC(C)=O>[NH2:29][C:3]1[CH:4]=[C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][C:27]=2[F:28])[NH:24][N:23]=[CH:22]3)=[O:17])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)c([N+](=O)[O-])c2)CC(=O)N1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)c(N)c2)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The product (222 mg, 0.5 mmol, 1.0 equiv.) from Example 76, Step 3 was dissolved in EtOAc (50 mL) and SnCl2 (380 mg, 2.0 mmol, 4 equiv.) and H2O (0.5 mL) were added. The mixture was refluxed for 3 h. After the reaction was cooled to room temperature, 2N NaOH was added and the mixture was stirred for 30 min. The biphasic solution was filtered through the Celite, and the phases were separated. The organic phase was washed twice with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give the title compound in 64% yield. MS (ES+) m/e 414 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]([S:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:40]=[N+:41]=[N-:42])(C)C>CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:42][N:41]=[N:40][N:24]=3)=[CH:15][CH:16]=2)[C:8]([S:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:27])=[O:26])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(S(=O)(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: CO
Product: CCCCc1nnc(S(=O)(=O)Cc2ccc(Cl)cc2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 17 %

Procedure:
The title compound was prepared from 3-n-butyl-5-(4-chlorobenzylsulfonyl)-4-[(2'-cyanobiphenyl- 4-yl)methyl]-4H-1,2,4-triazole (Step A) according to the procedure of Example 15, Step E, except that 3.5 equivalents of trimethyltin azide were added at the start, and the column was eluted with a gradient of 0-10% methanol in CH2Cl2. The product was obtained in 17% yield as a glass, which was transformed to a powder upon scraping: mp 180°-182° C. dec.; homogeneous by TLC in 4:1CH2Cl2 --MeOH; mass spectrum (FAB) m/e 548 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:8][CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[I:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([CH2:34][NH2:35])[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:19])[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1)[CH2:8][CH2:9][NH:35][CH2:34][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([I:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC=O)c1ccc(F)c(F)c1
Reactant: CN1CCC(CN)(c2ccc(I)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CNCCN(C(=O)OC(C)(C)C)c2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To a stirred solution of (3,4-difluorophenyl)-(2-oxo-ethyl)-carbamic acid-tert-butyl ester (1.23 g, 4.3 mmol) in MeOH (35 mL) under Ar at room temperature was added a solution of C-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-yl]-methylamine (1.49 g, 4.5 mmol, 1.05 eq.) in MeOH (10 mL). The mixture was stirred at room temperature for 5 h then NaBH4 (0.255 g, 6.75 mmol, 1.5 eq) was added and the resulting mixture was stirred for a further 1 h and then was quenched by the addition of 1N aqueous NaOH (40 mL). The mixture was extracted twice with Et2O (2×50 mL) and the combined organic extracts were washed with saturated brine (100 mL) and dried over Na2SO4. Filtration and concentration of the filtrate by rotary evaporation gave the crude product which was purified by flash column chromatography by eluting with 12% EtOAc/hexanes to give (3,4-difluoro-phenyl)-(2-{[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester (2.03 g, 76%) as a pale oil. MS (ESI): 585.9/587.0 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.C(N(C(C)C)CC)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:38][S:39]([O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Reaction time: 0.5 h

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-hydroxyethoxy]hexyl}-1,3-oxazolidin-2-one (200 mg) in dichloromethane (14 ml) under nitrogen at 0° was treated with diisopropylethylamine (0.10 ml) followed by methanesulfonyl chloride (0.04 ml). The mixture was stirred at 0° for 0.5 h and sat. sodium bicarbonate solution (30 ml) was then added. The mixture was extracted with dichloromethane (30 ml) and the organic extract dried (Na2SO4). The solvent was evaporated in vacuo to give the title compound (240 mg). LCMS RT=3.22 min, ES+ve 472 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:19][C:18]3[CH:17]=[N:16][N:15]([CH3:20])[C:14]=3[NH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([OH:29])=[O:28].[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:30]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][O:28][C:27](=[O:29])[CH2:26][CH2:25][C:3]2[CH:4]=[CH:5][C:6]([C:8]([N:10]3[CH2:19][C:18]4[CH:17]=[N:16][N:15]([CH3:20])[C:14]=4[NH:13][C:12]4[CH:21]=[CH:22][CH:23]=[CH:24][C:11]3=4)=[O:9])=[CH:7][C:2]=2[CH3:1])[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)OCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
WSCD (107 mg, 0.54 mmol) and DMAP (33 mg, 0.27 mmol) were added to a solution of 3-[2-methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionic acid from Example E45 (106 mg, 0.27 mmol) and 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester (81 mg, 0.32 mmol) in di-chloromethane (5 ml) and DIEA (0.095 ml, 0.54 mmol). The mixture was stirred for 3 h at room temperature, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; EtOAc) to yield the title compound (44 mg, 26%).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[N:20]1([C:26]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:27]=2[C:28](Cl)=[O:29])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH2:1]([O:5][C:6](=[O:19])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:28](=[O:29])[C:27]3[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:26]=3[N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: CCCCOC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)cc1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 4-Piperazin-1-yl-benzoic acid butyl ester (CAS: 86620-18-0) and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (example B) (yield :16%, MS (m/e): 497.3 (M+H, 100%)
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:41](Cl)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@H:9]([CH3:33])[C@H:10]([NH:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:11][O:12][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of (2R,3R)-3-(benzyloxy)-2-(tritylamino)butan-1-ol (4.33 g, 9.91 mmol) dissolved in 150 mL of CH2Cl2 was treated with triethylamine (1.52 mL, 10.9 mmol), tert-butyldimethylsilyl chloride (1.65 g, 10.9 mmol) and DMAP (122 mg, 1.00 mmol) and the reaction mixture was stirred under N2 overnight. The reaction mixture was then concentrated and the resulting material was dissolved in 50 mL of CH2Cl2 and washed successively with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 5-10% ethyl acetate/hexanes) gave 3.26 g of (2R,3R)-3-(benzyloxy)-1-{[tert-butyl(dimethyl)silyl]oxy}-N-tritylbutan-2-amine as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].C(Cl)(Cl)Cl>CN(C=O)C>[Cl:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([Cl:11])[CH:8]=1)[O:4][CH2:3][CH2:2][N:17]1[C:13](=[O:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16]1=[O:18]
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 1-(2-bromo-ethoxy)-3,5-dichloro-benzene (2.41 g, 8.93 mmol) and potassium phthalimide (2.00 g, 10.64 mmol) in DMF (7.6 mL) was heated at 85° C. for 1 h. The reaction was cooled to room temperature and chloroform was added. The organic solution was washed with 0.2 N aqueous NaOH followed by water. The organic solution was dried (Na2SO4), filtered, and concentrated. The residue was suspended in Et2O and the solid was collected by filtration to provide the title compound (2.21 g). 1HNMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.77 (m, 2H), 6.89 (m, 1H), 6.88 (m, 2H), 4.16 (t, 2H), 4.05 (t, 2H); MS 336 (M+).
Reaction SMILES: [P:1]([NH:9][NH2:10])(=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([O:20][CH2:21][C:22](=[CH2:26])[CH:23]([CH3:25])[CH3:24])[CH:13]=1>CCOCC>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][NH:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])=[C:14]([O:20][CH2:21][C:22](=[CH2:26])[CH:23]([CH3:24])[CH3:25])[CH:13]=1
Reactant: CCOP(=O)(NN)OCC
Reactant: C=C(COc1cc(Cl)ccc1C=O)C(C)C
Solvent: CCOCC
Product: C=C(COc1cc(Cl)ccc1C=NNP(=O)(OCC)OCC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of 11.8 g (0.070 mol) of diethyl phosphorohydrazidate in 140 mL ether was added 14.0 g (0.058 mol) of the product obtained in Step A. The reaction was stirred at room temperature for 30 minutes. The resultant precipitate was filtered and washed with ether (50 mL) and dried to afford 15.0 g of a white solid, mp 103° C. to 106° C.
Reaction SMILES: [I:1][C:2]1[C:7]([NH2:8])=[C:6](I)[N:5]=[CH:4][N:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[I:1][C:2]1[C:7]([NH2:8])=[C:6]([O:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(I)ncnc1I
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Nc1c(I)ncnc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in 1-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at 100° C. for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (2.0 g) as an oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][C:8]3([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[NH:14][CH2:13][CH2:12][N:9]3[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]23[NH:14][CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]2[N:6]([C:2]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])=[CH:3][CH:4]=2)[CH2:7]3)=[CH:16][CH:17]=1
Reactant: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C23Cn4c(C#C[Si](C)(C)C)ccc4C(=O)N2CCN3)cc1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (120 mg, 0.33 mmol), Pd(PPh3)2Cl2 (23 mg, 0.033 mmol) and copper(I) iodide (15 mg, 0.079 mmol) were added to a 10 mL round bottom flask that was then evacuated and then filled back with argon twice. Dry DMF (5 mL) was added and the solution degassed with argon for 10 minutes. Triethylamine (0.24 mL, 1.7 mmol) and trimethylsilylacetylene (0.24 mL, 1.7 mmol) were added and the resulting brown solution was degassed with argon for a further minute. The reaction flask was sealed and heated at 80° C. until full consumption of the starting material (4 hours; monitored by LCMS). The solution was diluted with ethyl acetate (50 mL) and washed with brine (3×15 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give a material that was purified by flash chromatography (2× Biotage SP4, 12 g cartridge, CH2Cl2 3 CV, gradient 0-10% MeOH in CH2Cl2 15 CV, hold for 5 CV) and (Biotage SP4, 12 g cartridge, gradient 50-100% EtOAc in hexanes 10 CV, hold for 15 CV) to give 10a-(4-methoxyphenyl)-8-[(trimethylsilyl)ethynyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a yellow solid (84 mg, yield 62%). ESI-MI m/z [M+H]+ 380.0.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Br:14][CH:15]([CH3:19])[C:16](Cl)=[O:17]>ClCCl>[CH:1]1([O:7][C:16](=[O:17])[CH:15]([Br:14])[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(Br)C(=O)Cl
Reactant: OC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Br)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of cyclohexanol (10.9 g, 10.9 mmol), pyridine (8.62 g, 10.9 mmol) in dichloromethane was added 2-bromopropionyl chloride (18.53 g, 10.9 mmol) at 0° C. The resulting mixture was stirred at room temperature for 1 hr. The product was partitioned between hexane and 10% citric acid. The organic phase was separated, dried over MgSO4 and concentrated to yield 2-bromo-propionic acid cyclohexyl ester, which was used in the following reaction without further purification.