Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]#[CH:10])(=O)=O.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:6]([N:20]1[CH2:21][CH2:22][N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)[CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C#CCCCOS(C)(=O)=O
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCCN1CCN(c2ccccc2)CC1
Yield: 71.7 %

Procedure:
A solution of pent-4-ynyl methanesulfonate (1.05 g), N-phenyl piperazine (1.02 g) and diisoproylethylamine (1.2 mL) in THF (5 mL) was heated to reflux overnight. The mixture was concentrated, diluted with aq. NaOH 2M (10 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 2:1→2:0) afforded 1-(pent-4-ynyl)-4-phenylpiperazine (1.03 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.CC([O-])(C)C.[K+].[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1>CS(C)=O>[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][O:25][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:19][CH2:18]1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: OCCN1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(OCCN2CCOCC2)nc1
Temperature: 95 °C
Yield: 9.4 %

Procedure:
To a solution of 6-chloronicotinic acid (Aldrich, 1.00 g, 6.35 mmol) and t-BuOK (1.42 g, 12.7 mmol) in DMSO (10.0 mL) was added 2-morpholinoethanol (1.5 mL, 12.7 mmol) at room temperature. The reaction mixture was then heated at 95° C. for 16 h. Additional t-BuOK (1.42 g, 12.7 mmol), 2-morpholinoethanol (1.54 mL, 12.7 mmol) and DMSO (10.0 mL) were added, and the reaction mixture was heated at 95° C. for another 24 h. The reaction mixture was then cooled to room temperature, poured into ice cold 4N aq. HCl solution and extracted with EtOAc (3×). The aqueous layer was concentrated in vacuo to near dryness and purified using preparative HPLC to give the title compound (150 mg, 9%) as a white solid after lyophilization. 1H NMR (DMSO-d6) δ 13.1 (br s, 1H), 8.74 (d, J=1.8 Hz, 1H), 8.21 (dd, J=8.6, 2.2 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 4.69 (br s, 4H), 3.96 (br s, 2H), 3.75-3.70 (m, 2H), 3.19 (br s, 4H); MS(ESI+) m/z 253.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:22]=2)=[CH:15][C:14]=1[C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: Cc1noc2ccc(Br)cc12
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc2onc(C)c2c1

Procedure:
Example 10 was prepared in a similar manner to Example 4 using 5-bromo-3-methyl-1,2-benzisoxazole (11 mg) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-pyrrolidin-1-yl-isonicotinamide (Intermediate 13, 16 mg) to give the title compound as an oil (6.6).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[Br-:15].[Br-:16].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2]>CO.C(Cl)Cl>[Br:15][C:6]1[C:5]([C:11]([F:12])([F:13])[F:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([Br:16])[C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(O)c(Br)c1C(F)(F)F
Yield: 15.5 %

Procedure:
2-Nitro-5-hydroxybenzotrifluoride (2.0 g, 9.7 mmol) was dissolved in a mixture of MeOH and CH2Cl2 (80 mL, 1:1) at 0° C. Benzyltrimethylammoniumtribromide (7.53 g, 19.3 mmol) and CaCO3 (2.0 g, 19.3 mmol) was added. The reaction mixture was heated at reflux for three days. The reaction was deemed complete by HPLC and LC/MS analysis and quenched by the addition of 1N HCl. The reaction mixture was washed with brine, dried with MgSO4 and purified on column (silica gel, with gradient elution of CHCl3/MeOH). This gave to 550 mg (16%) of 2,6-dibromo-3-trifluoromethyl-4-nitrophenol.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C@@H:18]([NH3+:20])[CH3:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][N:41]2[C:49]3[C:44](=[CH:45][C:46]([C:50](O)=[O:51])=[CH:47][CH:48]=3)[C:43]([CH3:53])=[C:42]2[CH3:54])=[CH:36][CH:35]=1)=[O:27])(C)(C)C>>[CH2:2]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C@@H:18]([NH:20][C:50]([C:46]2[CH:45]=[C:44]3[C:49](=[CH:48][CH:47]=2)[N:41]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]4[C:28]([C:26]([OH:27])=[O:25])=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:39][CH:38]=2)[C:42]([CH3:54])=[C:43]3[CH3:53])=[O:51])[CH3:19])[CH2:14][CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H]([NH3+])C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)C3CCN(C(=O)OCc4ccccc4)CC3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with ((S)-1-(1-((benzyloxy)carbonyl)piperidin-4-yl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-H-indole-5-carboxylic acid. ESI-MS (m/z): 643 [M+1]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C([NH:39][C@@H:40]([C:42](O)=[O:43])[CH3:41])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[NH2:39][C@H:40]([CH3:41])[C:42]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:43]
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)[C@@H](C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 39 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 60 mg Boc-D-Alanine via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 33.7 mg of 353 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:14]([C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=1)[CH2:8][OH:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CO)cc(C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
To 1 g of 3,5-di-t-butylbenzoic acid dissolved in THF (10 mL) was added at 25° C. a solution of 1M BH3 ·THF (4 mL), and the mixture was stirred at this temperature for 1.5 hours. The mixture was quenched with 1N NaOH (4 mL) and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and evaporated to give 3, 5-di-t-butylbenzyl alcohol as a clear oil which was used directly in the next step.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[O:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12.C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[N:1]1[S:2][N:3]=[C:4]2[C:9]([S:10]([O:13][C:14]3[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=3)[O:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cccc3nsnc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(benzo-2,1,3-thiadiazole-4-sulfonyloxy)-5-methylphenoxy]propanol (565 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.6 mL, 4.7 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a pale yellow oil (450 mg, 80%). 1H-NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.27 (d, J=7.1 Hz, 1H), 7.72 (t, J=8.6 Hz, 1H), 6.59 (s, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 4.17 (t, J=6.0 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.21 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(NCC(C)C)C(C)C.S(Cl)([Cl:26])(=O)=O>C1(C)C=CC=CC=1>[Cl:26][C:9]1[CH:8]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccc(C2CCOCC2)cc1
Agent: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCOCC2)cc1Cl
Temperature: 70 °C
Yield: 78.9 %

Procedure:
To a 30ml Toluene solution of 4-(4-tetrahydropyranyl) phenol 1 g (5.61 mmol) and diisobutylamine 0.08 ml (0.46 mmol) was added sulfuryl chloride 0.51 ml (6.35 mmol) over 3 hr period upon heating at 70° C. Stirring was continued at that temp. for 2 hr after the addition of sulfuryl chloride was complete. The solvent was removed under reduced pressure, diluted with ethyl acetate and washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, concentrated, chromatographed on silica gel (hexanes:ethyl acetate) to give 0.941 g of the title compound as while solid.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([NH2:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([N:23]1[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]1[C:29]#[N:30])=[O:22]>CN(C)C=O>[C:10]([C:5]12[CH2:4][CH2:3][C:2]([NH:1][CH2:20][C:21]([N:23]3[CH2:27][C@@H:26]([F:28])[CH2:25][C@H:24]3[C:29]#[N:30])=[O:22])([CH2:9][CH2:8]1)[CH2:7][CH2:6]2)(=[O:11])[NH2:12]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Reactant: NC(=O)C12CCC(N)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(N)=O)(CC1)CC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
4-Aminobicyclo[2.2.2]octane-1-carboxamide (50.0 mg) was dissolved in N,N-dimethylformamide (2 mL). To this solution, potassium carbonate (50.0 mg) was added, followed by dropwise addition of (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (70.0 mg) in N,N-dimethylformamide (1 mL) at room temperature. The mixture was stirred at room temperature for 2.5 hours and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant:chloroform:methanol=10:1) to give (2S,4S)-1-[[(4-carbamoylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (94.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[C:23]([CH3:24])=[N:22][NH:21][N:20]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI.C(I)C>CN(C=O)C.C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][C:19]3[C:23]([CH3:24])=[N:22][N:21]([CH3:25])[N:20]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1n[nH]nc1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nn(C)nc1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Yield: 26 %

Procedure:
To a suspension of the 6-chloro-2-(4-chlorophenyl)-3-((5-methyl-2H-1,2,3-triazol-4-yl)methyl)imidazo[1,2-a]pyridine (0.6-1.7 mmol, 1.0 eq) in DMF or THF (5-20 mL) was added potassium carbonate (3-5 eq) and either methyliodide or ethyliodide (3-5 eq) and the reaction mixture was heated at 75-85° C. for 18 h. After this time the reaction mixture was cooled and diluted with water (20-50 mL) and ethyl acetate (20-50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (10-30 mL) and the combined organic layers were dried over Na2SO4, concentrated and the residue was purified by chromatography (silica gel, heptane/ethyl acetate gradient) or reverse phase preparatory HPLC (acetonitrile/water gradient) to obtain the desired product. (0.14 g, 26% yield). M/e+ 372.1 for C18H15Cl2N5 (M+H)+; 1H-NMR (500 MHz, CDCl3, δ) 8.09 (d, J=2.0 Hz, 1H), 7.69-7.67 (m, 2H), 7.58 (d, J=9.5 Hz, 1H), 7.45-7.44 (m, 2H), 7.17 (dd, J=9.5, 2.0 Hz, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[N:18]=1.[H-].[Na+].[CH2:21]([N:23]([CH2:27][CH2:28][CH2:29]Cl)[CH:24]([CH3:26])[CH3:25])[CH3:22]>O1CCOCC1>[CH2:21]([N:23]([CH2:27][CH2:28][CH2:29][N:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[N:10]([CH3:13])[C:11](=[O:12])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:18][C:6]1=2)[CH:24]([CH3:26])[CH3:25])[CH3:22]
Reactant: CCN(CCCCl)C(C)C
Reactant: Cc1ccc2c(n1)Nc1ccccc1N(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN(CCCN1c2ccccc2N(C)C(=O)c2ccc(C)nc21)C(C)C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture consisting of 4.5 gm of 6,11-dihydro-2,6-dimethyl-5H-pyrido-[2,3-b][1,5]benzodiazepin-5-one, 60 ml of dioxane and 1.27 gm of 50% sodium hydride in mineral oil was stirred at 90° C. for 1 hour. Thereafter, 4.3 gm of 3-(N-ethyl-N-isopropyl-amino)-propyl chloride were added dropwise, and the mixture was refluxed for 17 hours. The reaction solution was then evaporated in vacuo, and the residue was purified over a silica gel column and recrystallized from petroleum ether, yielding 36% of theory of the compound named in the heading, which had a melting point of 104°-105° C.
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH2:11][CH:10]([NH:12]C(=O)CC2C=CC=CC=2)[C:9]1=[O:22])[CH:5]([CH3:7])[CH3:6])([OH:3])=[O:2].CN(C)C1C=CC=CC=1.C[Si](Cl)(C)C.P(Cl)(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O.C(O)(C)C.C(O)CCC>[NH2:12][CH:10]1[CH2:11][N:8]([CH:4]([C:1]([OH:3])=[O:2])[CH:5]([CH3:6])[CH3:7])[C:9]1=[O:22]
Reactant: CC(C)C(C(=O)O)N1CC(NC(=O)Cc2ccccc2)C1=O
Agent: C[Si](C)(C)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)C(C(=O)O)N1CC(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
1-(1-Carboxy-2-methylpropyl)-3-phenylacetamido-2-azetidinone (1.52 g.) and N,N-dimethylaniline (2.15 g.) were suspended in methylene chloride (12 ml.), and to the suspension was added trimethylsilyl chloride (0.88 g.). The solution was stirred for 30 minutes at ambient temperature and cooled to -50° C. Phosphorus pentachloride (1.1 g.) was added to the solution and the solution was stirred for 2 hrs. (the reaction temperature was elevated to about -30° C. during the stirring.). The solution was cooled to -50° C., and n-butyl alcohol (1.85 g.) was added to the solution, and then the solution was stirred for 2 hrs. (in this time, the reaction temperature was elevated to about -30° C.). The solution was cooled again to -50° C., and a solution preparing by dissolving sodium bicarbonate (1.3 g) in water (15 ml.), was added to the solution (in this time, the reaction temperature was elevated to about -25° C., and the solution indicated about pH 3). The solution was adjusted to pH 4 with sodium bicarbonate, and then the aqueous layer was separated out and washed with ether. The solution was evaporated to dryness under reduced pressure, keeping the temperature of the solution under 25° C. To the residue obtained was added isopropyl alcohol (15 ml.), and the mixture was filtered to obtain an insoluble material and a filtrate. The filtrate was evaporated to dryness under reduced pressure. This operation was repeated twice to give colorless powdery 3-amino-1-(1-carboxy-2-methylpropyl)-2-azetidinone (0.3 g.). These insoluble materials in isopropyl alcohol obtained above were combined and dissolved in a small amount of water, and the solution was adjusted to pH 2.5 with 1 N-hydrochloric acid. The aqueous solution was evaporated to dryness under reduced pressure at 25° C., and the residue obtained was treated with isopropyl alcohol in the similar manner as described above to recover an object compound (0.13 g.). Total yield was 0.43 g. This product was treated in a conventional manner to give its salt of D-camphor-10-sulfonic acid, and the salt was recrystallized from a mixture of acetone and ether to give D-camphor-10-sulfonic acid salt of the object compound. Mp 178° to 183° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]1[CH:18]=[C:13]2[CH:12]=[C:11]([C:21]([C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=3)=[CH:22][CH:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[NH:10][C:14]2=[N:15][CH:16]=1
Reactant: COc1cnc2c(c1)cc(C(=CC1CCOCC1)c1ccc(C(F)(F)F)cc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cnc2[nH]c(C(=CC3CCOCC3)c3ccc(C(F)(F)F)cc3)cc2c1
Yield: 99.9 %

Procedure:
A solution of 1-benzenesulfonyl-5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (260 mg, 0.48 mmol) in tetrahydrofuran (0.5 mL) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 2 mL, 2 mmol) was stirred at room temperature for 12 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with a saturated aqueous ammonium chloride solution and brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 5-methoxy-2-[2-(tetrahydro-pyran-4-yl)-1-(4-trifluoromethyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (193 mg, quant.) as a white solid: LC/MS m/e calcd for C22H21F3N2O2 [M+H]+ 403.42, observed 403.2.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1C=CC=CC=1>[CH:16]1([C:19]([N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9](=[O:11])[C:10]3=[CH:1][S:2][CH:3]=[C:4]23)=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: c1ccccc1
Product: O=C1Nc2ccccc2N(C(=O)C2CC2)c2cscc21

Procedure:
To a mixture of 10.0 g. of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of benzene is added 11 g. of cyclopropanecarbonyl chloride. The mixture is refluxed for 3 hours and then filtered. The filtrate is washed four times with aqueous sodium bicarbonate, the organic layer is dried over magnesium sulfate and then is filtered. The filtrate is evaporated to give the desired product as pale pink crystals, mp. 245°-247° C.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:16]
Reactant: O=C(Cl)CCCCCBr
Reactant: Nc1ccc(O)cc1
Product: O=C(CCCCCBr)Nc1ccc(O)cc1
Yield: 88 %

Procedure:
was prepared in 88% yield from 148.4 g (1.36 mol) of p-aminophenol and 145 g (0.68 mol) of 6-bromohexanoyl chloride according to the procedure of Example 1, part a, except that the addition was made at ambient temperature and the reaction was refluxed one hour, mp 124°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 4 h

Procedure:
33 g of 4-(2-Methoxy-5-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (97.8 mmol) were dissolved in 450 mL of methanol. 3 g of 10% Pd/C were added at room temperature under nitrogen atmosphere, and the reaction mixture was hydrogenated for 4 h. The reaction mixture was filtered over Celite, the was solvent evaporated and the remaining residue was treated with 100 mL of diisopropylether. Once crystallization started, the solvent was removed under reduced pressure and the remaining product dried thoroughly. This material was used in subsequent steps without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([N:21]1[C:31]2[NH:30][C:29]3[N:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27](=[O:36])[N:26]([CH3:37])[C:25]=2[CH:24]=[CH:23][CH:22]1[C:38]1[CH:42]=[CH:41][N:40]([Si](C(C)C)(C(C)C)C(C)C)[CH:39]=1)[CH3:20]>C1COCC1.CCOCC>[CH2:19]([N:21]1[C:31]2[NH:30][C:29]3[N:32]=[CH:33][CH:34]=[CH:35][C:28]=3[C:27](=[O:36])[N:26]([CH3:37])[C:25]=2[CH:24]=[CH:23][CH:22]1[C:38]1[CH:42]=[CH:41][NH:40][CH:39]=1)[CH3:20]
Reactant: CCN1C2=C(C=CC1c1ccn([Si](C(C)C)(C(C)C)C(C)C)c1)N(C)C(=O)c1cccnc1N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN1C2=C(C=CC1c1cc[nH]c1)N(C)C(=O)c1cccnc1N2
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Tetrabutylammonium fluoride in THF (1M, 0.36 mL) was added to a solution of 5,11-dihydro-1-ethyl-5-methyl-2-[1-(triisopropylsilyl)pyrrol-3-yl]-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.17 g) in dry THF (10 mL). After stirring the resulting mixture for 1 h, it was diluted with ether, washed with water, dried (anhyd Na2SO4), filtered, and evaporated. The residue was chromatographed over silica gel (ethyl acetate/hexanes, 1:1), and then crystallized from chloroform/hexanes to give 0.083 g of the title compound, mp 173°-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:16]C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)=[O:4].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1([NH2:16])[CH2:15][CH2:14][CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(NC(=O)OCc2ccccc2)CCCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(N)CCCC2(CC1)OCCO2
Yield: 76.9 %

Procedure:
66 mg of 8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester was dissolved in methanol and hydrogenated in an H-cube™ hydrogenation reactor (ThalesNano, Budapest, Hungary) at a hydrogen pressure of 100 bar at 40° C. over a cartridge with 10% palladium on charcoal. The mixture was evaporated to dryness to yield the crude title compound (32 mg).