Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][NH:15][CH2:16][CH2:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][CH2:27][CH2:28][C:29]1([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)OCC[O:30]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][N:15]([CH2:26][CH2:27][CH2:28][C:29]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)=[O:30])[CH2:16][CH2:17][CH:18]=1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC3=CCCN(CCCC(=O)c4ccc(F)cc4)C3)c2c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.5 g; 0.0062 mol), potassium carbonate (4.3 g; 0.031 mol), KI (0.06 g; 0.0004 mol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane (1.3 ml; 0.0064 mol) in dry dimethylformamide (30 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature, quenched with water and then extracted with diethyl ether. The organic extract was dried (MgSO4) and evaporated under vacuum. The residue was taken up in a solution of hydrochloric acid (37%; 6 ml) in methanol (30 ml). The resulting mixture was stirred for 2 hours at room temperature. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the solvent (methanol) was evaporated under vacuum. The residual alkaline aqueous solution was extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained (1,72 g). A solution of the compound in ethanol was saturated with gaseous hydrogen chloride. A white solid was precipitated. The title compound hydrochloride was collected by filtration, washed with ethanol and dried under vacuum.
Reaction SMILES: [C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[N+:27]([O:30][CH:31]([CH2:36][O:37][N+:38]([O-:40])=[O:39])[CH2:32][CH2:33][CH2:34]O)([O-:29])=[O:28].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:4][CH2:5]/[C:6](/[C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)=[C:7](/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)\[C:8]([O:10][CH2:34][CH2:33][CH2:32][CH:31]([O:30][N+:27]([O-:29])=[O:28])[CH2:36][O:37][N+:38]([O-:40])=[O:39])=[O:9])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])OCC(CCCO)O[N+](=O)[O-]
Reactant: CC(=O)OC/C(=C(\C(=O)O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\C(=O)OCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
To a solution of 1.72 g of (2Z)-4-(acetyloxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoic acid in 20 mL of CH2Cl2 at 0° C. was added 1.06 g of 4,5-bis(nitrooxy)pentyl alcohol, 225 mg of DMAP and 970 mg of EDCI. The mixture was stirred at RT for 2 h then quenched by addition of NH4Cl sat., extracted with EtOAc, washed with NaHCO3 sat., brine and dried over sodium sulfate. Purification by flash chromatography afforded 1 g of the titled compound as a white solid. 1H NMR (acetone-d6, 500 MHz): δ 7.77 (d, 2H), 7.43 (d, 2H), 7.18-7.16 (m, 3H), 7.08 (dd, 2H), 5.53-5.50 (m, 1H), 5.20 (s, 1H), 4.97 (dd, 1H), 4.69 (dd, 1H), 4.31 (m, 2H), 3.05 (s, 2H), 1.89 (m, 7H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.CC([N:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:27])=[CH:32][CH:33]=5)[CH:41]=4)[NH:22][C:17]=3[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cc(C=O)[nH]n2)cc1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Temperature: 65 °C
Yield: 70 %

Procedure:
Triethylamine (2.32 g, 23 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (11 mL) after five minutes, a solution of 1,1-dimethylethyl[4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamate in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (0.60 g, 70% yield). (Note that the BOC group was removed under the purification conditions.)
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[CH3:18].[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:2]4[CH:1]5[CH2:8][CH:5]([CH2:4][CH:3]=4)[CH2:6][CH2:7]5)=[C:10]([CH3:18])[CH:11]=3)=[O:14])[CH2:24][C:23]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cc(C(=O)O)ccc1C1=CCC2CCC1C2
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CCC2CCC1C2
Yield: 68.3 %

Procedure:
4-(Bicyclo[3.2.1]oct-2-en-2-yl)-3-methyl-benzoic acid of Step B (0.132 g, 0.545 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.111 g, 0.6 mmol) were reacted by in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from 1:1 ethyl acetate/petroleum ether afforded the title compound (0.152 g) as white crystals, m.p. 168–169° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:2].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:24][CH2:25][C@H:26]([OH:27])[C:28]3[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Reactant: CCOC(=O)CCNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Product: CCOC(=O)CCNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidin-1-yl)-benzoylamino]-propionic acid ethyl ester (which was obtained in Example 158) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp>95° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.1 Hz, 3 H), 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.54 (t, J=7.0 Hz, 2 H), 2.70–2.95 (m, 5 H), 2.94 (s, 3 H), 3.35–3.50 (m, 2 H), 3.80–3.95 (m, 2 H), 4.05 (q, J=7.1 Hz, 2 H), 4.65–4.75 (m, 1 H), 6.88 (d, J=8.2 Hz, 1 H), 6.95 (d, J=8.9 Hz, 2 H), 7.05 (dd, J=8.2, 1.9 Hz, 1 H), 7.22 (d, J=1.9 Hz, 1 H), 7.69 (d, J=8.9 Hz, 2 H), 8.26 (t, J=5.2 Hz, 1 H); MS (ES) m/z: 549.2 (MH+); HRMS Calcd. for C26H37N4O7S (MH+): 549.2377. Found: 549.2369.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11].C1COCC1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[S:27]>C(N(CC)CC)C>[NH2:3][C:4]1[C:8]([NH:9][C:26]([NH:25][C:19]2[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[S:27])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11]
Reactant: Cc1sc(C)c(N)c1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1sc(C)c(NC(=S)Nc2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 3,4-diamino-2,5-dimethylthiophene dihydrochloride, 30 ml of anhydrous THF and 0.49 g of triethylamine was stirred at room temperature for 30 minutes and then admixed with 0.569 g of 2,6-dichlorophenyl isothiocyanate. After the mixture had been heated to 40° C. for 30 minutes, it was stirred at room temperature for approx. 18 hours, the solvent was distilled off, the residue admixed with water and the precipitate filtered off and purified by column chromatography on silica gel using a mixture consisting of equal parts by volume of toluene and ethyl acetate. After the solvent had been distilled off, a foamy, amorphous product of m.p. 143–148° C. was obtained which, after melting, solidified again with a new m.p. of >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:17][C:18]#[N:19]>C(O)(=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=3)[CH2:17][C:18]#[N:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 56 %

Procedure:
A stirred suspension of 3-nitrophthalic anhydride (0.24 g, 1.13 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.25 g, 1.13 mmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange gum which was dissolved in methylene chloride (10 mL) and was washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting solid was dried in vacuo (60° C., <1 mm) to afford 0.25 g (56%) of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid: mp 155.5°-157° C.; 1H NMR (CDCl3) δ 8.20-8.09 (m, 2 H), 8.02-7.86 (m, 1 H), 7.15-7.02 (m, 2 H), 6.88-6.76 (m, 1 H), 5.64 (dd, J=6.3, 10.6 Hz, 1 H), 4.09 (q, J=7 Hz, 2 H), 3.85 (s, 3 H), 3.84 (dd, J=10.6, 16.7 Hz, 1 H), 3.26 (dd, J=6.3, 16.7 Hz, 1 H), 1.46 (t, J=7 Hz, 3 H); 13C NMR (CDCl3) δ 165.3, 162.3, 150.1, 148.7, 144.9, 135.7, 133.5, 129.0, 128.1, 127.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7; Anal. calcd for C20H17N3O6. Theoretical: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.59; H, 4.22; N, 10.65.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[O:13][C:12]2=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]12CC(CC1)=C[CH:22]=2>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][N:17]3[CH:22]=[CH:21][N:19]=[N:18]3)[O:13][C:12]2=[O:20])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1
Yield: 59.4 %

Procedure:
(5R)-3-(4-t-Butylphenyl)-5-azidomethyloxazolidin-2-one (400 mg, 1.46 mM) was dissolved in dioxane (8 ml), treated with norbornadiene (1.3 g, 14.1 mM) and heated under reflux for 6 hours. After removal of the solvent, the residue was dissolved ethyl acetate, and purified by flash chromatography on silica, eluting with the same solvent. Relevant fractions were combined to give the desired product (260 mg, mp 140–142°). MS (EI): 300 (M+) for C16H20N4O2
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]2)=[O:9])=[C:6]([O:26][CH2:27][CH2:28][O:29][CH3:30])[N:5]=1>C1COCC1.O>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:6]1[N:5]=[C:4]([NH:2][CH3:1])[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:7]=1[C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)=[O:9]
Reactant: CN
Reactant: COCCOc1nc(Cl)c([N+](=O)[O-])cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(OCCOC)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
Methylamine (2 M in THF; 400 μL, 0.80 mmol) is added to 6-chloro-2-(2-methoxy-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (150 mg, 0.35 mmol) in THF (10 mL). After 45 min at rt the reaction mixture is diluted with water, concentrated and filtered. The filtercake is washed with water and dried.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:11](=[O:17])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[I:18]I>C(Cl)(Cl)(Cl)Cl.N1C=CC=CC=1>[I:18][C:10]1[C:11](=[O:17])[N:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:9]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: II
Reactant: CSc1nccc(-c2cc(=O)n3n2CCC3)n1
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1nccc(-c2c(I)c(=O)n3n2CCC3)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 3-(2-methylsulfanyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 20, (4.7 g, 19.1 mmol), in carbon tetrachloride/pyridine (140 mL of 1:1 mixture) is added dropwise a solution of iodine in carbon tetrachloride/pyridine (80 mL of 1:1 mixture). After stirring at 0° C. for 30 min, the ice-bath is removed at the mixture was stirred at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was poured into aqueous saturated Na2S2O3. The aqueous phase is extracted with EtOAc (×3). The combined organic phases are dried (MgSO4), filtered and concentrated in vacuo. The resulting yellow solid is purified by silica gel chromatography (5% MeOH/chloroform) to afford 4.2 g of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.72 (d, J=5.1 Hz, 1H), 7.97 (d, J=5.1 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 4.10 (t, J=6.9 Hz, 2H), 2.74 (dddd, J=6.9, 6.9, 6.9, 6.9 Hz, 2H), 2.62 (s, 3H); ESI+ MS: m/z (rel intensity) 375.0 (100, M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][CH2:45][CH2:46][NH2:47]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:47][CH2:46][CH2:45][F:44])=[O:21])([CH2:18][CH2:19]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCF
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Agent: Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NCCF)(CC1)CC2
Yield: 77.5 %

Procedure:
In a similar manner to Example 13, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-fluoroethylamine hydrochloride (11.2 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-2-fluoroethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (33.9 mg).
Reaction SMILES: [CH:1]([SH:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH3:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20]Cl)[C:10]1=[O:22]>CO>[CH3:8][C:9]1([CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH2:20][S:4][CH:1]([CH3:3])[CH3:2])[C:10]1=[O:22]
Reactant: CC(C)S
Reactant: CC1(C)C(=O)N(CCl)C(=O)c2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)SCN1C(=O)c2ccccc2C(C)(C)C1=O

Procedure:
1.17 gm of isopropylmercaptan were added to a solution of 0.83 gm of sodium methylate in 50 ml of methanol. After shaking the resulting mixture, 3.3 gm of 4,4-dimethyl-2-chloromethyl-2H,4H-isoquinoline-1,3-dione were added, and the mixture was refluxed for 15 minutes. The precipitated sodium chloride was suction-filtered off, the filtrate was evaporated, and the residue was purified on a silicagel column (eluant: chloroform/cyclohexane=1:1). After evaporation of the eluate a colorless oil was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:28][C@H:27]([O:29][CH2:30][C:31](OC(C)(C)C)=[O:32])[CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:26][C@H:27]([O:29][CH2:30][CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)CO[C@H]1C[C@@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](OCCO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
cis-tert-Butyl ({3-[8-amino-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}oxy)acetate (0.4 mmol, 200 mg) was dissolved in THF (2 mL) and charged with LiAlH4 (4 mmol, 4 mL, 1 M in THF) at −78° C., and stirred under rt for 1 h before the reaction mixture was heated to 50° C. for 16 h. Mixture was charged with EtOAc and allowed to stir at rt for 10 min, followed by an addition of Na2SO4.10H2O. The reaction mixture was passed through a pad of Celite and concentrated under reduced pressure. The crude oil was purified by silica gel column chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 1-3% MeOH in DCM), yielding the title compound as a colorless oil; NMR 1H NMR (400 MHz, CD3OD) δ 7.47(td, 2H), 7.43-7.42 (m, 1H), 7.39-7.36 (m, 2H), 7.33-7.29 (m, 1H), 7.25 (t, J=2.0 Hz, 1H), 7.19 (td, J=1.2 Hz, 8 Hz, 1H), 7.13 (dd, J=2.4 Hz, 8.0 Hz, 1H), 6.98 (d, J=4.8 Hz, 1H), 5.17 (s, 2H), 4.16 (p, J=7.2 Hz, 1H), 3.66-3.65 (m, 2H), 3.51 (t, J=2.4 Hz, 2H), 3.50-3.43 (m, 1H), 2.88-2.81 (m, 2H), 2.46-2.38 (m, 2H). MS (ES+): m/z 431 (100) [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=3)[N:11]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:10]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccn1
Reactant: Cc1[nH]c2cc(Cl)ccc2c1Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1-c1ccccn1
Reaction time: 0.17 h

Procedure:
3-(3-Bromo-phenylsulfanyl)-6-chloro-2-methyl-1H-indole (0.500 g, 1.4 mmol) along with K2CO3 (0.488 g, 3.5 mmol) and 2-fluoropyridine (87 μL, 2.1 mmol) were dissolved in DMF (2 mL) and reacted in a microwave at 200° C. for 20 minutes. The reaction was returned to the microwave at 200° C. for an additional 10 minutes. Standard workup followed by silica gel chromatography (0-100% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]Br>ClCCl>[CH2:1]([N:8]1[C:16]([Br:24])=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CNc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)CNc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Benzyl-2-chloroadenine (0.30 g, 1.12 mmol), glycine methyl ester hydrochloride (0.72 g, 5.73 mmol) and diisopropylethylamine (1.48 g, 11.47 mmol) were added to n-butanol (10 ml), and the mixture was stirred in an autoclave at 150° C. for 19 hours. The solvent was removed and the residue was poured into water. The solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-2-methoxycarbonylmethylaminoadenine (0.06 g) as a brown tar. Thus obtained 9-benzyl-2-methoxycarbonylmethylaminoadenine was dissolved in dichloromethane (10 ml) and to the solution was added bromine (0.05 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography to give 9-benzyl-8-bromo-2-methoxycarbonylmethylaminoadenine (0.06 g) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C:10]3=[C:9]([C:24]([O:26]CC)=[O:25])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO>[C:20]([O:19][C:17]([N:15]1[CH2:14][CH2:13][CH2:12][N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][C:9]([C:24]([OH:26])=[O:25])=[C:10]2[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 65 °C
Yield: 94.6 %

Procedure:
A mixture of Intermediate 39A (0.81 g, 2.10 mmol) and lithium hydroxide monohydrate (706 mg, 16.8 mmol) in methanol (20 mL) was heated at 65° C. for 5 hours. After evaporation of methanol, the residue was dissolved in brine. Concentrated HCl (2.5 mL) was added carefully to acidify and the mixture was extracted twice with DCM. The combined organic extracts were dried and evaporated to give Intermediate 39B as white solid (0.71 g 95% yield). LCMS (+ESI) m/z 357.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.[Br:24]NC(=O)CCC(N)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH2:10][Br:24])=[CH:4][CH:3]=1
Reactant: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Reactant: NC(=O)CCC(=O)NBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnnc1C(CBr)=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-1-propene (61.46 g, 0.197 mole) [prepared in Step C], N-bromosuccinamide (35.06 g, 0.197 mole) and catalytic amount of azobis isobutyronitrile or benzoyl peroxide in carbon tetrachloride (1.2 liters) was heated to reflux in an inert atmosphere for a period of 2 hours. The reaction mixture was cooled to ambient temperature and the solid from the reaction was filtered. The filtrate was concentrated under reduced pressure and the solid obtained was recrystallized from toluene-hexane to give 72 g (93%) of the title compound as white crystals; m.p.=159°-160° C.