Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46](N1CCC(C(=O)NC2C=CC(Br)=CC=2)CC1)=[O:47])([CH3:44])([CH3:43])[CH3:42].BrC1C=CC(N)=CC=1.[C:72]([O:76][C:77]([N:79]1[CH2:84][CH2:83][CH:82]([C:85](O)=[O:86])[CH2:81][CH2:80]1)=[O:78])([CH3:75])([CH3:74])[CH3:73]>>[C:46](=[O:47])([O:45][C:41]([CH3:42])([CH3:43])[CH3:44])[O:76][C:72]([CH3:75])([CH3:74])[CH3:73].[C:72]([O:76][C:77]([N:79]1[CH2:84][CH2:83][CH:82]([C:85]([N:27]2[C:17]3[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=[C:15]([C:12]4[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=5)[CH2:30][C:31]5[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=5)=[N:14][CH:13]=4)[C:16]=3[CH2:29][CH2:28]2)=[O:86])[CH2:81][CH2:80]1)=[O:78])([CH3:75])([CH3:74])[CH3:73]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Br)cc2)CC1
Agent: Nc1ccc(Br)cc1
Product: CC(C)(C)OC(=O)OC(C)(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)C3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc1

Procedure:
From bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (87 mg) and 4-(4-bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (prepared from 4-bromoaniline, WSCI and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester, and then di-tert-butyl carbonate, 80 mg), in the same manner as Example 1-D-08, a crude product of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbonyl)-piperidine-1-carboxylic acid tert-butyl ester was obtained, and then the PMB groups and BOC group were removed according to the above Deprotection method 1, to obtain the desired compound (D-64) as a colorless powder (11 mg, 10%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:20]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(CO)c2C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h

Procedure:
In a 10 dram vial, added 1-7 (300 mg, 0.795 mmol) to pyridine (3975 μl) followed by acetic anhydride (225 μl, 2.385 mmol) and DMAP (9.71 mg, 0.080 mmol). After 1 h, LCMS showed complete consumption of R1 desired product. Partitioned between 10 mL H2O and 10 mL EtOAc, separated layers. Back-extracted aqueous with 1×5 mL EtOAc. Washed combined organics with 5×5 mL H2O. Dried combined organics over Na2SO4, filtered, concentrated to give a pale yellow oil. Purification by normal-phase HPLC (40 g ISCO column, 0-50% EtOAc:Hexanes) gave 7-1 as a clear, colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:3].CCCCCC.C(O)(C)C.C(NCC)C>>[CH3:3][N:2]([CH2:4][C@@H:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:1].[CH3:3][N:2]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([NH2:15])[CH:9]=[CH:8][C:7]=2[CH2:6]1)[CH3:1]
Reactant: CN(C)CC1CCc2cc(N)ccc2C1
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: CCNCC
Product: CN(C)C[C@@H]1CCc2cc(N)ccc2C1
Product: CN(C)C[C@H]1CCc2cc(N)ccc2C1

Procedure:
6-[(Dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine was optically resolved, using CHIRALCEL OD-H (20 mm×250 mm) (hexane/isopropanol/diethylamine=75/25/0.1) to obtain 156 mg of (6R*)-6-[(dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine, and 159 mg of (6S*)-6-[(dimethylamino)methyl]-5,6,7,8-tetrahydronaphthalen-2-amine.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1.[BH4-].[Na+].O>CC(C)=O.CO>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccncc2)cc1
Reactant: O=S1(=O)CCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: O=S(=O)(O)CCCN1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 4-phenylpyridine (15.5 g, 0.1 mol) in acetone (100 mL) was added 1,3-propane sultone (12.2 g, 0.1 mol) at room temperature. The mixture was then heated at reflux temperature overnight. The resultant suspension was cooled to room temperature. The solid was collected by filtration and washed with acetone. To a solution of the solid (31 g) in methanol (500 mL) was added sodium borohydride (10 g, 260 mmol) portionwise, and the mixture was stirred at room temperature for 2 h. Distilled water (50 mL) was added to destroy the excess of sodium borohydride. The mixture was diluted with methanol (200 ml), and neutralized with Amberlite IR-120 ion-exchange resin (H+ form, 300 g). A white precipitate was formed. The precipitate and the resin were removed by filtration and treated with distilled water (400 mL) at ˜100 ° C. The mixture was filtered and the residual resin was washed with hot distilled water (2×200 mL). The filtrates and washings were combined and concentrated to dryness. The residue was co-evaporated with methanol (3×200 mL), and then recrystallized from ethanol-water {8:2 (v/v)} to afford 4-phenyl-1-(3′-sulfopropyl)-1,2,3,6-tetrahydropyridine as white crystals (26 g, 93%). The 1H and 13C NMR spectra were in agreement with the structure.
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[NH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])=[CH:16][CH:15]=1>>[ClH:13].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[C:10]([CH:8]2[CH2:7][CH2:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:9]2)=[O:12])=[CH:18][CH:19]=1
Reactant: CNCCCc1ccc(Cl)cc1
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Product: CN(CCCc1ccc(Cl)cc1)C(=O)C1CCc2[nH]cnc2C1
Product: Cl

Procedure:
By a similar procedure as described in Example 65, the title compound was prepared from 4,5,6,7-tetrahydrobenzimidazole-5-carboxylic acid and 3-(4-chlorophenyl)propylmethylamine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[S:32][CH:33]=[C:34]([C:36]2[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=2)[NH2:39])[N:35]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:39][C:38]2[CH:40]=[CH:41][CH:42]=[C:36]([C:34]3[N:35]=[C:31]([CH3:30])[S:32][CH:33]=3)[CH:37]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: Cc1nc(-c2cccc(N)c2)cs1
Product: Cc1nc(-c2cccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)c2)cs1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(2-methylthiazol-4-yl)aniline in step 1. MS: 424.37 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].Cl.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[CH3:30])[N:18]=[C:17]2[N:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]1[CH3:41]>C(O)C>[C:1]([OH:8])(=[O:7])[CH:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:11].[F:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:19]2[N:18]=[C:17]([N:31]3[CH2:40][CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]3[CH3:41])[C:16]3[C:21](=[C:12]([O:11][CH3:10])[CH:13]=[CH:14][CH:15]=3)[N:20]=2)=[C:24]([CH3:30])[CH:25]=1
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cccc2c(N3CCc4ccccc4C3C)nc(Nc3ccc(F)cc3C)nc12
Agent: Cl
Solvent: CCO
Product: O=C(O)CC(O)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 0.27 g of maleic acid(2.33 mM) and 50 ml of ethanol, 1.20 g of the compound (2.80 mM) prepared in Example 34 was dropwise added. The resultant was stirred at room temperature for 12 hours and concentrated under a reduced pressure. The residue produced was crystallized by adding ethyl ether and ethyl acetate, to give 1.15 g of the title compound.
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][NH:11][CH2:12]2)(=[O:5])=[O:4].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[C:17]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH2:12]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCc2c(cccc2NS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
To a solution of 5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.87 g, 0.011 mol) in dichloromethane at 0° C. was added acetic anhydride (1.2 ml, 0.013 mol) and triethylamine (3.4 ml, 0.024 mol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the aqueous phase extracted with further portions of ethyl acetate. The combined organic extracts were dried (MgSO4) and evaporated to afford an oil. This was dissolved in methanol (15 ml) and treated with aqueous sodium carbonate solution (7%, w/w, 15 ml) and the mixture stirred for 16 hours at room temperature, after which time the methanol was removed under reduced pressure, the pH was adjusted to pH 8 with 2N hydrochloric acid and the product was extracted with ethyl acetate (2×). The combined organic extracts were dried (MgSO4) and evaporated to give an oil which was purified on silica gel, eluting with dichloromethane:methanol (95:5, v/v) to give the title compound as an oil (2.0 g, 68%). Rf 0.20 (dichloromethane:methanol 95:5, v/v). MS m/z 269 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[O:7][C:8]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[C:11](Br)[C:9]=2[CH:10]=1)(=[O:5])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[O:45]1[CH2:49]CCC1.[OH2:50]>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>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[O:7][C:8]2[C:9](=[C:11]([C:49]([OH:45])=[O:50])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=1)(=[O:5])=[O:4]
Reactant: C1CCOC1
Reactant: COc1ccc(Br)c2cc(S(=O)(=O)N(C)C)oc12
Reactant: O
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)O)c2cc(S(=O)(=O)N(C)C)oc12

Procedure:
Prepared from 4-bromo-7-methoxybenzofuran-2-sulfonic acid dimethylamide (1.0 g), triphenylphosphine (0.28 g), bis(triphenylphosphine)palladium (II) chloride (0.15 g) and triethylamine (4.2 ml) in tetrahydrofuran/water (40 ml/20 ml). The title compound was obtained as a white solid (0.79 g).
Reaction SMILES: [P:1]([CH:5]1[CH2:9][CH2:8][CH:7](P(O)(O)=O)[O:6]1)([OH:4])([OH:3])=[O:2].P([O-])(OC)[O:15][CH3:16].[H-].[Na+]>COC1CCC(OC)O1>[P:1]([CH:5]1[CH2:9][CH2:8][CH:7]([O:15][CH3:16])[O:6]1)([OH:4])([OH:3])=[O:2]
Reactant: O=P(O)(O)C1CCC(P(=O)(O)O)O1
Reactant: COP([O-])OC
Agent: COC1CCC(OC)O1
Agent: [H-]
Agent: [Na+]
Product: COC1CCC(P(=O)(O)O)O1

Procedure:
To make 2,5-diphosphonotetrahydrofuran (i.e. n is 2), step (a) is suitably accomplished by adding dimethyl phosphite to a cool slurry of sodium hydride in 2,5-dimethoxytetrahydrofuran under an inert atmosphere such as nitrogen or argon and heating the resulting reaction mixture to form 2-phosphono-5-methoxytetrahydrofuran as a first intermediate. Step (b) is suitably accomplished by adding bromotrimethyl silane to said first intermediate and stirring the resulting mixture under an inert atmosphere such as nitrogen or argon, thereby forming di-(trimethylsilyl)2-phosphono-5-bromotetrahydrofuran as a second intermediate. Step (c) is suitably accomplished by adding triisopropyl phosphite to said second intermediate and heating the mixture under an inert atmosphere such as nitrogen or argon, thereby forming 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran. Diphosphonotetrahydrofuran may be produced by adding a concentrated acid, such as hydrochloric acid to the 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran and refluxing the acid solution. 2,6-Diphosphonotetrahydropyran (i.e. n is 3) and 2,7-Diphosphonooxepane (i.e. n is 4) may be produced in similar fashion, respectively using 2,6-dimethoxytetrahydropyran and 2,7-dimethoxyoxepane rather than 2,5-dimethoxytetrahydrofuran as a starting material.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.CN(C=O)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[N:21][C:22]([Cl:27])=[C:23]([Cl:26])[C:24]=1[Cl:25]>[Zn].O>[Cl:25][C:24]1[C:23]([Cl:26])=[C:22]([Cl:27])[N:21]=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 133.1 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stir bar was charged with NiCl2.6H2O (105 mg, 0.442 mmol), 2,2′-bipyridine (150 mg, 0.960 mmol), DMF (15 mL) and water (2 mL). The resulting mixture was allowed to stir for 5 min, and then zinc dust (2.006 g, 30.7 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 15 min until a very dark blue/black solution was present. Solid 3,4,5,6-tetrachloropicolinic acid (2.017 g, 7.7 mmol) was added through the top of the reactor. The reaction mixture was allowed to stir at 27° C. for 5.25 h, and the crude reaction mixture was filtered through a course frit filter and washed with DMF (5 mL). The resulting filtrate was diluted with an equal volume of 10% HCl (aq) which resulted in the precipitation of a light yellow solid that was collected by filtration. The solid was collected by vacuum filtration to give the title compound (2.32 g, 81.5%) that was 61.5% pure as analyzed by calibrated HPLC.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH2:28][OH:29]>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH:28]=[O:29]
Reactant: OCc1cc(Br)ccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1Cl
Reaction time: 5 h
Yield: 85.8 %

Procedure:
Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH2Cl2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (1.28 g, 86%). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J=8.6 Hz, 1 H), 7.65 (dd, J=8.3, 2.5 Hz, 1 H), 8.04 (d, J=2.5 Hz, 1 H), 10.41 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>CC1C=CC(C)=CC=1.CC1C=CC=C(C)C=1.CC1C(C)=CC=CC=1>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Solvent: Cc1cccc(C)c1
Solvent: Cc1ccc(C)cc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 125 °C
Yield: 94.64 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in xylenen (70 mL) respectively and heated to 125° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.89 g, yield: 94.64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:33][N:32]=[C:31]4[NH:41][CH:42]=[C:43]([CH3:44])[C:30]=34)[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]([NH:13]C(=O)OC(C)(C)C)([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:13][C:10]([CH3:12])([CH3:11])[CH2:9][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:21]([N:23]1[CH2:24][CH2:25][N:26]([C:29]2[C:34]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][N:32]=[C:31]3[NH:41][CH:42]=[C:43]([CH3:44])[C:30]=23)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CC(C)(C)NC(=O)OC(C)(C)C)c4ccc(Cl)cc4)CC3)c12
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CC(C)(C)N)c4ccc(Cl)cc4)CC3)c12
Reaction time: 1 h
Yield: 101.4 %

Procedure:
(R)-tert-Butyl 4-(4-chlorophenyl)-2-methyl-5-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-5-oxopentan-2-ylcarbamate (0.040 g, 0.065 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added. The reaction was stirred for 1 hour and then concentrated to dryness. The resulting oil was dissolved in minimal DCM, and added to a stirring solution of 1M HCl in ether. The resulting solid was collected by filtration, washed with ether, and dried to give (R)-4-amino-2-(4-chlorophenyl)-4-methyl-1-(4-(3-methyl-5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)pentan-1-one (0.034 g, 89% yield) as the dihydrochloride salt. MS ESI (+) m/z 517 detected.
Reaction SMILES: C([NH:4][CH:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[C:9]([Cl:22])[CH:8]=[CH:7][C:6]1=2)(=[O:3])C.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O.Cl>[OH2:3].[OH2:3].[NH2:4][C:5]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[C:9]([Cl:22])[CH:8]=[CH:7][C:6]1=2
Reactant: CC(=O)NC1c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NC1(Cc2ccccc2)c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Product: O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 2 g of 10-acetamido-7-chloro-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 40 ml of anhydrous dimethyl sulphoxide, maintained at 20° C. under a nitrogen atmosphere, is added 0.61 g of 60% sodium hydride and the mixture is stirred for 90 minutes. 0.8 ml of benzyl chloride are then added dropwise and the stirring is continued for 24 hours. The reaction medium is then poured onto 50 ml of ice-water, then acidified using 1N hydrochloric acid (12 ml). The precipitate formed is filtered off, washed with water and then with acetone, and dried. The crude product thus obtained (1.8 g) is taken up in 20 ml of 6N hydrochloric acid and maintained at reflux for 2 hours. The insoluble product is filtered off, washed with water and recrystallized from 45 ml of a mixture of ethanol and water (1/2 by volume) to give 0.31 g of 10-amino-10-benzyl-7-chloro-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one dihydrate in the form of a white powder melting at 241° C. (Analysis, C20H19ClN4O3.0.82 HCl, % calculated C: 60.23; H: 4.80;
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](O)=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+]>>[CH2:10]([O:9][C:3]1[CH:4]=[C:5]([O:21][CH2:18][C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)[CH:7]=[CH:8][C:2]=1[Br:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc(Br)c(O)c1
Reactant: BrCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
Using a procedure similar to that described in Example 17.a., except using 4-bromoresorcinol and using two equivalents of benzyl bromide and potassium carbonate, the named compound was prepared as a white solid; MS: 369; NMR: 5.0 (s, 2), 5.1(s, 2), 6.47(d, d, J1 =8, J2 =2.6, 1), 6.6 (d, J=2.7, 1), 7.2-7.5 (m, 11).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:25])[CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:14]=2[C:13]2[CH2:22][CH2:23][CH2:24][C:12]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>ClCCl.CC(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[F:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]([CH2:10][C@@H:9]([NH2:8])[CH3:25])[C:12]3[CH2:24][CH2:23][CH2:22][C:13]=3[C:14]=2[C:15]=1[F:21]
Reactant: C[C@@H](Cn1c2c(c3c(F)c(F)ccc31)CCC2)NC(=O)OC(C)(C)C
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: ClCCl
Product: C[C@H](N)Cn1c2c(c3c(F)c(F)ccc31)CCC2
Temperature: 25 °C
Yield: 220.8 %

Procedure:
A solution of (S)-4-[2-(tert-butoxycarbonylamino)propyl]-7,8-difluoro-1,2,3,4-tetrahydrocyclopent[b]indole (0.4 g, 1.1 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (15 mL) was stirred at room temperature for 1 h. The mixture was made basic by the addition of aqueous sodium hydroxide solution (2 N), then extracted with dichloromethane (3×50 mL). The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to give an orange oil. The oil was dissolved in 2-propanol (5 mL) and the solution was heated to boiling then fumaric acid (0.38 g, 3.3 mmol) was added. The mixture was cooled to room temperature and filtered The filter-cake was washed (2-propanol, ether) and dried in vacuo to give the title compound (0.89 g, 68%) as a pale orange solid. mp. 154-156° C. (dec.); NMR δH (400 MHz, DMSO-d6) 1.13 (3H, d, J 7 Hz), 2.43-2.52 (2H, m), 2.78-2.94 (4H, m), 3.5-3.57 (1H, m), 4.13 (1H, d, J 8 Hz), 4.29 (1H, dd, J 6.5 Hz), 6.55 (2H, s), 7.01-7.10 (1H, m) and 7.26-7.31 (1H, m).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][Si:20]([CH3:35])([CH3:34])[CH2:21][CH2:22][O:23][C:24](ON1C(=O)CCC1=O)=[O:25].O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([C:24]([O:23][CH2:22][CH2:21][Si:20]([CH3:35])([CH3:34])[CH3:19])=[O:25])[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Br)c1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: C[Si](C)(C)CCOC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 96.1 %

Procedure:
A solution of 1-(2-bromo-4-nitrophenyl)piperazine dihydrochloride (1.9 g, 5.8 mmol) in acetonitrile (50 mL) was treated with 1-({[2-(trimethylsilyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (1.5 g, 5.9 mmol) followed by water (15 mL) and sodium carbonate (1.9 g, 18 mmol) and stirred at 20° C. for 6 h. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give a residue. This material was purified by flash column chromatography to give the desired product (2.4 g, 87%) as a solid. [TEOC: (2-(trimethylsilyl)ethoxy)carbonyl]