Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:5]([O:6]1)[CH2:4][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:21][CH2:20]3)[CH:9]=1)[CH2:2]2.O.NN>CCO>[CH:5]12[CH2:7][CH:1]([O:6]1)[CH2:2][N:3]([C:8]1[CH:17]=[C:16]3[C:11]([N:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:18][CH:19]3[CH2:20][CH2:21][CH:22]([NH2:25])[CH2:23][CH2:24]3)[CH:9]=1)[CH2:4]2
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NC1CCC(Oc2cc(N3CC4CC(C3)O4)cc3nccnc23)CC1
Yield: 77.8 %

Procedure:
To a solution of 2-[4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexyl]isoindoline-1,3-dione (800 mg, 1.700 mmol) in EtOH (10 mL) was added hydrazine monohydrate (85.10 mg, 83.35 μL, 1.700 mmol) and the reaction was stirred at reflux overnight, then concentrated, diluted with DCM, and filtered. The filtrate was concentrated, and purified on a 40 g silica gel cartridge with 0-50% (20% NH3/MeOH) to yield 4-[7-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)quinoxalin-5-yl]oxycyclohexanamine (450 mg, 77.8%) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) ∂ 8.65 (d, J=1.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 6.83 (q, J=2.6 Hz, 2H), 4.83 (t, J=6.0 Hz, 4H), 3.87-3.60 (m, 5H), 3.34 (dt, J=8.7, 6.6 Hz, 1H), 3.01-2.83 (m, 1H), 2.23 (dq, J=11.3, 5.8, 4.8 Hz, 2H), 2.07 (d, J=8.7 Hz, 1H), 1.92-1.62 (m, 6H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Br>CC(C)=O>[CH:19]1([CH2:23][NH:25][CH2:28][CH:30]([OH:32])[CH2:31][NH:25][C:23]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:13][CH2:12]2)=[CH:22]3)=[O:24])[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]1
Reactant: BrCC1CO1
Reactant: NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(NCC(O)CNCC1CCCCC1)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to scheme 7. To an ice-cold solution of 1.0 g (3.0 mmol) of 4-benzylpiperidinyl indole-5-carboxamide in acetone was added 15 mmol of powdered KOH followed by 3.0 mmol of epibromohydrin and the mixture was stirred for 30 min. The mixture was filtered and the solution was evaporated. The residue was dissolved in ethyl acetate, washed with water, dried and evaporated. After purification by silica gel column chromatography 435 mg of epoxide was obtained. MS (M+ 373).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.30 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzothiazole, 0.14 g of methylmercaptan sodium salt and 3 ml of DMF was stirred at room temperature for 20 minutes. To the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate three times. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 2-[3-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)benzothiazole (hereinafter, referred to as the present compound 5).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH:32]=[O:33])=[CH:5][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]4[CH2:20][CH2:19][CH2:18][C:17](=CC5C=CC=CC=5)[C:12]4=[N:13][C:14]=3[C:15]=2[N:16]=1.C[OH:35]>ClCCl>[NH2:2][C:3]1[C:4]([CH:32]=[O:33])=[CH:5][C:6]2[CH2:7][CH2:8][C:9]3[C:10]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:11]4[CH2:20][CH2:19][CH2:18][C:17](=[O:35])[C:12]4=[N:13][C:14]=3[C:15]=2[N:16]=1
Reactant: CO
Reactant: CCCCc1c2c(nc3c1CCc1cc(C=O)c(N)nc1-3)C(=Cc1ccccc1)CCC2
Agent: Cl
Solvent: ClCCl
Product: CCCCc1c2c(nc3c1CCc1cc(C=O)c(N)nc1-3)C(=O)CCC2
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 0.46 g (1 mmol) of 2-amino-11-benzylidene-7-n-butyl-5,6,8,9,10,11-hexahydrobenzo[b][1,10]phenanthroline-3-carboxaldehyde HCl salt (XX) in 40 mL of dichloromethane and 20 mL of methanol is stirred at approximately -78° C. and ozone is bubbled through the orangish-yellow solution. When the color of the reaction mixture changes to pale greenish-yellow, the solution is immediately purged by bubbling in N2 for 5 minutes. Dimethylsulfide (1.0 mL) is added and the reaction mixture is allowed to warm to room temperature. The solvents are removed by rotary evaporation and the residue is triturated with 100 mL of ether, yielding 0.39 g (100%) of product.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[NH:21][CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1.[C:35]([O:39][CH3:40])(=[O:38])[CH:36]=[CH2:37]>CN(C=O)C.[Cl-].[Na+].O>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=6)=[CH:25][CH:26]=5)[N:21]([CH2:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])[CH:20]=4)=[O:18])=[C:12]3[CH2:11][S:10]2)[CH:4]=1
Reactant: C=CC(=O)OC
Reactant: O=C(c1ccn2c1CSC2c1cccnc1)c1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCn1cc(C(=O)c2ccn3c2CSC3c2cccnc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Sodium hydride (95%, 37.4 mg, 1.48 mmol) was added to a solution of 3-(pyridin-3-yl)-7-[6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (0.50 g, 1.14 mmol), prepared according to the method of Example 28, in DMF (30 mL). The reaction mixture was stirred for 30 min. at ambient temperature, and then methyl acrylate (0.40 mL, 4.56 mmol) was added. The reaction mixture was poured into brine and extracted three times with ethyl acetate. The combined organic layers where dried over MgSO4, filtered, and concentrated in vacuo. 3-(Pyridin-3-yl)-7-[1-(2-carbomethoxyethyl)-6-(4-fluorophenyl)indol-3-ylcarbonyl]-1H,3H-pyrrolo[1,2-c]thiazole (190 mg, 32%) was obtained by flash chromatography on silica gel (5 g, 40%, then 60%, then 80% ethyl acetate, hexanes). 1H NMR (CDCl3, 300 MHz) δ2.93 (t, 2 H, J=6, 8 Hz), 3.68 (s, 3H), 4.53 (dd, 3H, J=6, 11 Hz), 4.7 (dd, 1H, J=2, 15 Hz), 6.38 (d, 1H, J=3 Hz), 6.43 (s, 1H), 6.78 (d, 1H, J=3 Hz), 7.15 (t, 2H, J=9, 10 Hz), 7.35 (dd, 1H, J=5, 8 Hz), 7.5 (dd, 2H, J=3, 10 Hz), 7.6-7.1 (m, 3H), 7.95 (s, 1H), 8.45 (dd, 1H, J=1, 9 Hz), 8.6-8.68 (m, 2H). MS (DCI/MH3) m/e 526 (M+H)+.
Reaction SMILES: C[C@@H:2]1[O:9][C:7](=[O:8])[C@H:6]([CH3:10])[O:5][C:3]1=O.O.[C:12]1(C)[CH:17]=[CH:16]C(S(O)(=O)=O)=[CH:14][CH:13]=1.C(O)C1C=CC=CC=1>>[C:7]([O:9][CH2:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)(=[O:8])[C@H:6]([CH3:10])[OH:5]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Solvent: O
Product: C[C@H](O)C(=O)OCc1ccccc1

Procedure:
Commercially available L-lactide 1 (16 g, 0.14 mol) and p-toluenesulfonic acid monohydrate (catalytic amount) in benzyl alcohol (40 mL, 0.38 mol) was heated to 110° C. overnight. Excess benzyl alcohol was removed under vacuum to obtain a light yellow oil. The desired product was distilled under vacuum (0.9 mm Hg, 85-95° C.) to obtain 50.3 g of 2 as a clear oil. The distilled oil was used without further purification.
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:10][C:4]=2[O:3]1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:23])=[O:14])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 8.00 g (35.1 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid in 40 ml tetrahydrofurane and 0.4 ml N,N-dimethyl formamide, 3.86 ml (45.0 mmol) oxalyl chloride was added dropwise at 0° C. within 10 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 34 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 7.20 g (90%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide were obtained.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6](=[O:34])([O:10][CH2:11][O:12][C:13](=[O:33])[CH2:14][CH2:15][CH:16]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[P:17]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18])SCC>>[CH2:20]([O:19][P:17]([CH:16]([P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:15][CH2:14][C:13]([O:12][CH2:11][O:10][C:6]([Cl:4])=[O:34])=[O:33])([O:22][CH2:23][CH3:24])=[O:18])[CH3:21]
Reactant: CCOP(=O)(OCC)C(CCC(=O)OCOC(=O)SCC)P(=O)(OCC)OCC
Reactant: O=S(=O)(Cl)Cl
Product: CCOP(=O)(OCC)C(CCC(=O)OCOC(=O)Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sulfuryl chloride (687 μL, 8.49 mmol) was added drop-wise to 61 (2.03 g, 4.24 mmol). The neat reaction was stirred at room temperature for 2.5 hr. The excess sulfuryl chloride was removed under reduced pressure resulting in chloroformate 62 (1.87 g, 97%) that was used without purification. 1H NMR (400 MHz, CDCl3): δ 1.35 (t, J=7.1, 12H), 2.17-2.36 (m, 2H), 2.53 (tt, J=23.8, 6.5, 1H), 2.80 (t, J=7.5, 2H), 4.15-4.24 (m, 8H), 5.82 (s, 2H). 31P NMR (162 MHz, CDCl3) δ 23.72 (s, 2P).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47](B4OC(C)(C)C(C)(C)O4)=[CH:46][CH:45]=3)=[O:42])=[CH:36][CH:35]=2)=[O:33])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>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.O>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:3]=[C:2]([C:47]1[CH:48]=[CH:49][C:44]([NH:43][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[O:33])=[CH:35][CH:36]=3)=[O:42])=[CH:45][CH:46]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Reactant: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)c5cc(F)c(-c6cccnc6)cc5n4)cc3)cc2)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-6-fluoro-4-morpholin-4-yl-7-pyridin-3-yl-quinazoline (90 mg, 0.000259 mol), 1-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-3-[4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea (144.7 mg, 0.0003114 mol), cesium carbonate (212.3 mg, 0.000647 mol), DMF (5 mL) and water (2.5 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (9.07 mg, 0.0000131 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 5% MeOH in chloroform) to yield the title compound (15 mg, 6%) 1H NMR (300 MHz, DMSO-d6): δ 9.05 (s, 1H), 9.0 (s, 1H), 8.93 (brs, 1H), 8.68-8.72 (m, 1H), 7.92-8.73 (m, 5H), 7.52-7.64 (m, 5H), 7.35 (d, J=8.1 Hz, 2H), 3.85 (s, 8H), 3.46-3.57 (m, 4H), 2.24-2.37 (m, 4H), 2.19 (s, 3H); LC-MS (ESI): Calculated mass: 646.2; Observed mass: 647.2 (RT: 0.11 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:7]2[CH2:8][C@H:3]1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:12][O:13][NH2:14].N1C=CC=CC=1>C(O)C>[CH3:12][O:13][N:14]=[C:6]1[CH2:5][CH2:4][C@H:3]2[CH2:8][C@@H:7]1[C:2]2([CH3:10])[CH3:1]
Reactant: CC1(C)[C@@H]2CCC(=O)[C@H]1C2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Yield: 89.9 %

Procedure:
To a solution of (1S,5R)-6,6-dimethylnorpinan-2-one (3.09 g, 22.35 mmol) in ethanol (70 mL) was added O-methylhydroxylamine hydrochloride (2.05 g, 24.59 mmol) and pyridine (1.29 mL, 15.92 mmol). Heated reaction mixture to 80° C. for 4 hours. Removed solvent under reduced pressure. Diluted residue with 1N HCl and extracted twice with ether. The combined organic phases were washed with aqueous saturated NaHCO3, dried (MgSO4), filtered, concentrated in vacuo to afford 3.36 g of a colorless oil (mixture of oxime isomers) that was used without further purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1.[H-].[Na+].Br[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38]>CN(C=O)C>[O:38]=[C:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36](=[O:37])[N:28]1[CH2:27][CH2:26][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3[nH]2)C1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3ccccc3n2CCN2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C

Procedure:
Tert-butyl 3-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (4.36 mmol, 1.3 g) was added to a 50 mL oven-dried round-bottomed flask equipped for stirring under nitrogen. DMF (15 mL) was added and the solution was cooled to 0° C. NaH (4.80 mmol, 192 mg) was then added in one portion and the resultant solution was stirred at 0° C. for 0.5 hr. At this time 2-(2-bromoethyl)isoindoline-1,3-dione (5.01 mmoles, 1.27 g) was added; the ice bath was removed and the reaction solution was allowed to warm to room temperature and stirred for 16 hrs. The reaction was then heated to 100° C. and allowed to stir for an additional 16 hrs. Analysis of the reaction solution by LC/MS indicated about an approx. 10% conversion to the desired title compound (129A). The reaction was cooled to rt and then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na2SO4 and filtered. This filtrate was collected, concentrated, and dried in-vacuo affording tert-butyl 3-(1-(2-(1,3-dioxoisoindolin-2-yl)ethyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (129A) as a mixture of products that was carried onto the next step without further purification. ESI-MS: m/z 475.3 (M+H)+.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)[CH2:2]1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:22][CH:21]=1.N12CCN(CC1)CC2>CN(C)C=O.C(OCC)(=O)C>[Si:30]([O:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=2)=[CH:21][CH:22]=1)([C:43]([CH3:45])([CH3:46])[CH3:44])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(OCC2CO2)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(O)COc2ccc(CCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Temperature: 70 °C
Yield: 58.7 %

Procedure:
A mixture of 1,2-epoxy-3-[4-(tert-butoxycarbonyl)phenoxy]propane (5.11 g, 20.4 mmol) [S. P. Connors, et al., J. Med. Chem., 1991, 34, 1570] and 3-(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (7.97 g, 20.4 mmol) in N,N-dimethylformamide (50 ml) was treated with 1,4-diazabicyclo[2,2,2]octane (0.45 g) and the resulting mixture was heated at 70° C. for 48 hours. The cooled mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 95:5) gave 7.67 g (58%) of the title material as oil.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:27]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:28])[C:3]1=[O:20]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)[C@@H](NC(=O)C2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, cyclohexane carboxylic acid chloride and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white solid after removal of the solvent: m.p. 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:48][N:47]=[N:46][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
A mixture of 4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.1 g), dibutyltin oxide (0.011 g), azidotrimethylsilane (0.74 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.035 g, 31%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=5[O:27][CH2:28][CH:29]5[CH2:30][CH2:31]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:34])[CH2:37][CH2:36]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)C5(O)CC5)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A170) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8][C:7]=2[C:31]=1[CH3:32].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9]([NH:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:8][C:7]=2[C:31]=1[CH3:32]
Reactant: NCCN1CCCC1
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccncc1-3
Product: COc1ccc2c3c(c(NCCN4CCCC4)nc2c1C)C(=O)c1ccncc1-3

Procedure:
This compound was prepared from toluene-4-sulfonic acid 3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (Example 18c-1) and 1-(2-aminoethyl)pyrrolidine in a similar manner to Example 18d. The desired product was obtained as a reddish powder. ESI−MS: m/z 389 (MH+); 1H-NMR (CDCl3): δ1.86 (4H, m), 2.50 (3H, s), 2.72 (4H, m), 2.90 (2H, t, J=6.5 Hz), 3.89 (2H, quartet like, J=ca 6.5 Hz), 4.02 (3H, s), 7.12 (1H, d, J=9 Hz), 7.18 (1H, brt, J=ca 5 Hz), 7.54 (1H, dd, J=4.5 Hz, 1 Hz), 8.04 (1H, d, J=9 Hz), 8.80 (1H, d, J=4.5 Hz), 9.27 (1H, brs).