Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][C:5]1[C:14]2[CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH2:23][O:24][C:25]([C@:27]([OH:30])([CH2:28][CH3:29])[C:19]=4[CH:18]=[C:17]3[C:13]=2[N:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([OH:31])[CH:9]=[CH:10]2)=[O:26].[C:32]([O:40][CH2:41]Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1>CN(C=O)C>[C:32]([O:40][CH2:41][O:31][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]3[C:17]4[N:16]([CH2:15][C:14]3=[C:5]([CH2:4][CH3:3])[C:6]=2[CH:7]=1)[C:21](=[O:22])[C:20]1[CH2:23][O:24][C:25](=[O:26])[C@@:27]([CH2:28][CH3:29])([OH:30])[C:19]=1[CH:18]=4)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[N:35][CH:34]=1
Reactant: CCc1c2c(nc3ccc(O)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Reactant: O=C(OCCl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c2c(nc3ccc(OCOC(=O)c4cccnc4)cc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13 %

Procedure:
NaH (0.012 g, 0.51 mmol, 1.0 eq) was added portion wise to a solution of SN-38, (S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione [4150] (0.20 g, 0.51 mmol, 1.0 eq) in DMF (2 ml) under N2 atmosphere at 0° C. The resulting reaction mixture was stirred at 0° C. for an additional 30 min. To the reaction mixture, chloromethyl nicotinate [259] (0.087 g, 0.51 mmol, 1.0 eq) dissolved in DMF was added dropwise while maintaining the temperature at 0° C. The reaction was then allowed to come to RT and stirred overnight. The reaction mass was quenched with addition of water. The reaction mixture was extracted with DCM (2×100 ml). The organic layers were combined and washed with brine, dried over Na2SO4 and evaporated. The resultant crude product was purified on column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-column chromatography (2% MeOH: DCM, silica gel 100-200 mesh) to yield a pale yellow solid, (S)-((4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinolin-9-yl)oxy)methyl nicotinate [305] (0.036 g, 13%).
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]([O:22]N3C4C=CC=CC=4N=N3)=O)([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.[C:43]12([NH2:53])[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH2:44]1)[CH2:50]2>>[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[CH2:13][CH2:14][C:15]([C:20]([NH:53][C:43]34[CH2:44][CH:45]5[CH2:51][CH:49]([CH2:48][CH:47]([CH2:46]5)[CH2:52]3)[CH2:50]4)=[O:22])([CH2:18][CH2:19]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: NC12CC3CC(CC(C3)C1)C2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)NC34CC5CC(CC(C5)C3)C4)(CC1)CC2
Yield: 74.3 %

Procedure:
In a similar manner to Example 4, (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 adamantanamine (17.1 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-adamantylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (38.2 mg).
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:5]1[CH:4]=[CH:3][C:2]([CH2:1][C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:7][CH:6]=1)([O-:15])=[O:14]
Reactant: c1ccc(Cc2c[nH]cn2)cc1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(Cc2c[nH]cn2)cc1

Procedure:
Prepared according to Arch. Pharm. 1975, 308, 755-759 by reacting 4-benzyl-1H-imidazole in fuming 100% nitric acid at -10 to -5° C. (30 minutes).
Reaction SMILES: C([O:3][P:4]([CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:26]1=[O:32])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])C.Br[Si](C)(C)C>ClCCl>[C:26]1(=[O:32])[N:25]([CH2:24][P:4]([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[OH:5])[C:30](=[O:31])[CH2:29][CH2:28][CH2:27]1
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CCCC1=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)CCCC1=O
Yield: 97.6 %

Procedure:
0.11 g (0.23 mmol) of (glutarimidomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester was dissolved in 4 ml of dicloromethane and the solution was stirred overnight in the presence of 2 ml of bromotrimethylsilane. The solvent was removed by evaporation and the residue was dissolved in 5 ml of acetone/water (9:1). The solvent was removed by evaporation and this treatment was repeated once more to give 0.1 g of (glutarimidomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of a foam.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[OH:8][CH:1]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3ccc(C(=O)c4ccccc4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCN(c2cccc3ccc(C(O)c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
The title product of example 43 (0.121 g, 0.366 mmol) was dissolved in ethanol (3 mL) and sodium borohydride (0.025 g, 0.66 mmol) was added. The mixture was stirred 1 hour at ambient temperature, then it was concentrated at reduced pressure at 40° C. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic layer was washed with water and brine; then it was dried over magnesium sulfate and concentrated to a light yellow oil. The oil was purified by flash chromatography on silica gel (1×4 inches). Elution with 50% ethyl acetate/hexane removed a fast moving component which was not identified. Continued elution with ethyl acetate gave 0.066 mg of the title product as a light tan oil which solidified. This solid was recrystallized from chloroform/ether to afford 0.033 mg (27%) of the title product as a light tan solid: mp 162.5°-163° C. Analysis calculated for C22H24N2O·0.25 H2O: C, 78.42; H, 7.33; N, 8.31. Found: C, 78.52; H, 7.06; N, 8.31.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:37]([CH3:40])(=[O:39])=[O:38])[C:14]1[C:33]([CH:34]2[CH2:36][CH2:35]2)=[CH:32][C:17]2[C:18]([C:28](=[N:30][OH:31])[NH2:29])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[O:20][C:16]=2[CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH:34]1([C:33]2[C:14]([N:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[S:37]([CH3:40])(=[O:38])=[O:39])=[CH:15][C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)=[C:18]([C:28](=[NH:29])[NH:30][OH:31])[C:17]=3[CH:32]=2)[CH2:35][CH2:36]1
Reactant: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=NO)c2cc1C1CC1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCCCO)c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To a solution of Example 16B (0.760 g, 1.289 mmol) in tetrahydrofuran (12 mL) was added 1 M tetrabutylammonium fluoride in tetrahydrofuran (3.22 mL, 3.22 mmol) in a fast drip, and the resulting yellow solution was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was further washed with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to a clear oil that crystallized upon standing. Trituration with 1:2 v/v dichloromethane/hexane afforded the title compound as a white powder (0.588 g, 92%). MS (ESI+) m/z 476 (M+H)+, (ESI−) m/z 474 (M−H)−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13].[NH2:14][OH:15]>CO>[OH:15]/[N:14]=[C:12](\[NH2:13])/[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: NO
Reactant: N#CCCCCNc1ccccn1
Solvent: CO
Product: N/C(CCCCNc1ccccn1)=N\O
Temperature: 40 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
5-(Pyridin-2-ylamino)pentanenitrile (1.00 g; 5.71 mmoles) was dissolved in methanol (10 mL) and hydroxylamine (1.4 mL of a 50% aqueous solution; 22.83 mmoles) was added. The reaction mixture was stirred at 40° C. under nitrogen for 2 days. The solvent was removed under vacuum and the resulting oil was placed under vacuum at 40° C. for 6 hours. The product (1Z)-N′-hydroxy-5-(pyridin-2-ylamino)pentanimidamide (A) (1.16 g; 98%) was obtained as a pale yellow oil. 1H NMR (DMSO-d6) δ 8.68 (1H, s, br), 7.91–7.95 (1H, m), 7.29–7.35 (1H, m), 6.35–6.45 (3H, m), 5.25–5.35 (2H, s, br), 3.15–3.23 (2H, m), 1.97 (2H, t, J=7.5 Hz), 1.45–1.60 (4H, m).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]#[N:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:2]=[CH:3][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:25][N:24]=[N:23][N:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:6]=1
Reactant: Cc1oc(C#N)cc1COc1ccc(-c2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1oc(-c2nnn[nH]2)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A mixture of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carbonitrile (148) (100 mg, 0.35 mmoles), sodium azide (27 mg, 0.415 mmoles) and potassium carbonate (62 mg, 0.45 mmoles) in dimethylformamide (5 ml) was heated at 90° C. for 96 hours then at 120° C. for 24 hours. The mixture was evaporated and the residue purified by HPLC to afford compound 149 as a white solid (64 mg). LC/MS System D; Rt=9.53 mins, m/2 (ES+)=333 (M+H for C19H16N4O2).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:13])[CH:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[C:14](O)(=O)[CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:14]1[O:13][C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[C:8]([C:9]([OH:11])=[O:10])[N:12]=1)[CH2:16][CH2:17][CH3:18]
Reactant: NC(C(=O)O)C(O)c1ccccc1
Reactant: CCCCC(=O)O
Product: CCCCc1nc(C(=O)O)c(-c2ccccc2)o1

Procedure:
Prepared starting from DL-3-phenylserine hydrate following sequentially general procedures W, X with pentanoic acid, Y and Z. LC-MS-conditions 02: tR=0.95 min; [M+H]+=246.45.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:19])[CH3:18])[CH:15]=3)[N:10]([C:20]([NH:22][C:23]3[S:24][C:25]([Cl:28])=[CH:26][N:27]=3)=[O:21])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[CH:15]=3)[N:10]([C:20]([NH:22][C:23]3[S:24][C:25]([Cl:28])=[CH:26][N:27]=3)=[O:21])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C(C)O)cc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C1(CCN(C(C)=O)C1)CN2C(=O)Nc1ncc(Cl)s1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
The 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-(1-hydroxyethyl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (22.3 mg, 0.053 mmol) obtained in Step 2 of Example 401 was dissolved in methylene chloride (0.5 mL). Thereafter, Dess-martin periodinane (27.0 mg, 0.0635 mmol) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred at the same temperature as above for 1 hour. Thereafter, an aqueous solution of sodium sulfite was added to the reaction solution, and the mixed solution was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (21.7 mg, 99%) in the form of a white solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][C:8](=[O:15])[C:9](=[N:13][OH:14])[C:10](=[O:12])[CH3:11].S(OC)(OC)(=O)=O.O>C(OC)(C)(C)C.CN(C=O)C>[CH3:1][O:14][N:13]=[C:9]([C:10](=[O:12])[CH3:11])[C:8](=[O:15])[CH3:7]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)C(=NO)C(C)=O
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(C)=O)C(C)=O
Temperature: -5 °C
Yield: 89 %

Procedure:
In a 20 l vessel, 4.5 kg (32.6 mol) of potassium carbonate were suspended in 3.2 l of methyl tert-butyl ether and a liter of DMF. With stirring, the mixture was cooled to from 0 to −10° C. A solution of 4128 g (32 mol) of pentane-2,3,4-trione 3-oxime, 2 l of DMF and 4032 g (32 mol) of dimethyl sulfate was then metered in at an internal temperature of <25° C. over a period of 2 hours. The mixture was stirred at room temperature for another 3.5 hours. A further 20 l of water were then added, the upper, organic phase was removed, the aqueous phase was washed with 2 l of methyl tert-butyl ether, the combined organic phases were washed with 1 l of 5% strength hydrochloric acid and the solvent was distilled off. This gave 4214 g of the title compound in a purity of 96.6% (GC area percent), corresponding to a yield of 89%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:12]=[O:13])=[N:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:14](O)[CH2:15][OH:16].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[N:5]=1
Reactant: OCCO
Reactant: COc1ccc([N+](=O)[O-])nc1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 884.2 %

Procedure:
A mixture of 0.55 g (0.3 mmol) 3-methoxy-6-nitro-pyridine-2-carbaldehyde, 0.8 ml (15 mmol) of ethylene glycol, and 10 mg (catalytic amount) of p-toluene sulfonic acid was refluxed in 50 ml of toluene using a Dean-Stark trap to trap water. After 90 minutes, the reaction mixture was cooled to room temperature and the solvent evaporated. The residue was chromatographed on silica using 5:1 (chloroform/ethyl acetate) as the elutant. Appropriate fractions were combined and evaporated to yield 0.6 g of 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine as an oil. TLC: Rf=0.9 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.40 (d, 1H), 6.30 (s, 1H), 4.30 (m, 2H), 4.10 (m, 2H), 4.0 (s, 3H). Mass Spectrum: m/e=227.2 (p+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])[C:5]([Cl:26])=[CH:4][N:3]=1.[CH3:27][O:28][CH2:29][CH2:30][N:31]1[CH2:37][CH2:36][C:35]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:34]=2[CH2:33][CH2:32]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][C:10]=2[O:11][CH2:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:42][C:39]2[CH:40]=[CH:41][C:34]3[CH2:33][CH2:32][N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH2:37][CH2:36][C:35]=3[CH:38]=2)=[N:3][CH:4]=1
Reactant: N#CCCOc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: O
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OCCC#N)n3)cc2CC1
Yield: 75 %

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-morpholin-4-yl-phenoxy]-propionitrile (84 mg, 0.00021 mol), 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (47 mg, 0.00021 mol), and 10-Camphorsulfonic acid (58 mg, 0.00025 mol) in Isopropyl alcohol (2.0 mL) was irradiated in a CEM microwave (140° C., 30 min). The mixture was diluted with 2 mL water and 0.5 mL satd. sodium bicarbonate, then extracted 2×10 mL DCM, dried over sodium sulfate and conc. onto 1 g Celite. Chromatography (ISCO, Amine-capped SiO2, 14 g, 25-100% EtOAc:Hex) afforded 3-(2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-5-morpholin-4-yl-phenoxy)-propionitrile as a light pink solid (91 mg, 74%). MP: 91-96° C., LCMS 578 (M+H); 1H-NMR (CDCl3): 8.23 (d, 1H, J=8.8 Hz), 8.02 (s, 1H), 7.52 (s, 1H), 7.37 (s, 1H), 7.18 (d, 1H, J=7.9 Hz), 7.00 (d, 1H, J=8.0 Hz), 6.85 (s, 1H), 6.56 (d, 1H, J=8.8 Hz), 6.50 (s, 1H), 4.28 (t, 2H, J=6.3 Hz), 3.88 (m, 4H), 3.53 (t, 2H, J=6.3 Hz), 3.38 (s, 3H), 3.14 (m, 4H), 2.90 (m, 6H), 2.72 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:7])#[CH:2]
Reactant: CCNCC
Reactant: C#Cc1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: C#Cc1cccc(C(=O)N(CC)CC)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 1.49 ml (14.4 mmol) of diethylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of diethyl ether, the ether layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=5/1 to 3/1) using silica gel to obtain 1.3 g of 3-ethynyl-N,N-diethylbenzamide which is a desired product as pale yellow liquid. (Yield: 92%)
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:9][CH3:10])[O:7][CH3:8].Cl[CH2:16][CH2:17][CH2:18][CH3:19].C[O-].[Na+]>CO>[CH2:16]([NH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][CH2:5][Si:6]([O:11][CH3:12])([O:7][CH3:8])[O:9][CH3:10])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCCl
Reactant: CO[Si](CCC(C)(C)CN)(OC)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCNCC(C)(C)CC[Si](OC)(OC)OC
Temperature: 125 °C
Yield: 77.2 %

Procedure:
In a 1 liter 3-necked flask equipped with a magnetic stirrer, heating mantle thermometers and condenser was added 664.1 g (3 moles) of 4-amino-3,3-dimethylbutyltrimethoxysilane and 69.4 g (0.75 mole) of 1-chlorobutane. With stirring, the flask contents were slowly heated to 125° C. and maintained at that temperature for a total of 13 hours. A gas chromatograph of a sample of the flask contents at that point indicated all of the chlorobutane had been consumed in the reaction with the aminofunctional silane. The flask was cooled to room temperature and 162 g of a 25% solution of sodium methoxide in methanol (0.75 mole of sodium methoxide) was added drop-wise by means of an addition funnel. After stirring for 30 minutes the flask contents were pressure filtered and distilled, yielding after removal of methanol and excess 4-amino-3,3-dimethylbutyltrimethoxysilane, 160.7 g of N-butyl-4-amino-3,3-dimethylbutyltrimethoxysilane (bp 90-94° C. at 1 mm Hg, 58% yield). The structure was confirmed by gc-mass spectroscopy and 1H and 13C nmr spectroscopy.
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>CCO.O1CCOCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1-c1cccnc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1-c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
Tin(II) chloride (11.86 g, 62.6 mmol) was added portionwise over 5 min to a stirred mixture of 3-(2-methyl-5-nitrophenyl)pyridine (2.86 g, 15.0 mmol) in EtOH (100 ml) and 1,4-dioxane (100 ml) at 0° C. The mixture was then stirred overnight, gradually warming to room temperature, and then concentrated under reduced pressure. 20% Aqueous NH3 solution (200 ml) and EtOH (300 ml) were added and again the mixture concentrated under reduced pressure. EtOAc (300 ml) was added and the mixture heated to reflux, the solids were filtered off and the process repeated twice more. The combined organic filtrates were concentrated under reduced pressure and the resulting crude residue was purified by column chromatography on silica, using 3% MeOH in dichloromethane as the eluent, to yield 4-methyl-3-(pyridin-3-yl)phenylamine (1.22 g, 44%): δH (360 MHz, CDCl3) 2.15 (3H, s), 6.56 (1H, d, J 2.4), 6.65 (1H, dd, J 8.0 and 2.4), 7.07 (1H, d, J 8.1), 7.31 (1H, dd, J 7.8 and 4.7), 7.62 (1H, dt, J 7.8 and 2.0), 8.53-8.60 (2H, m); m/z (ES+) 185 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](Oc2ccc(N)c(F)c2)CC1
Reaction time: 6 h

Procedure:
Palladium (10 wt. %) on carbon (500 mg) was added in one portion to a solution of 4-(3-fluoro-4-nitro-phenoxy)-cyclohexanecarboxylic acid ethyl ester (2.6 g, 8.35 mmol) in ethanol (75 mL) and the mixture was stirred under a hydrogen atmosphere for 6 h. The reaction mixture was filtered and concentrated in vacuo to leave a residue. The residue was purified by column chromatography, using a gradient of 20-50% EtOAc and isohexane as eluent, to give the title compound as a pale yellow solid (2.0 g, 85%)
Reaction SMILES: [CH:1]1([CH:6]([OH:10])[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:12][C@H:13]([C:15]([C:17]1([NH2:42])[C:23](=[O:24])[N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]2[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=2[N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:18]1=[O:41])=[O:16])[CH3:14]>>[CH:1]1([CH:6]([OH:10])[C:7]([NH:12][C@H:13]([C:15]([C:17]2([NH2:42])[C:23](=[O:24])[N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]3[CH:31]=[CH:32][CH:33]=[CH:34][C:20]=3[N:19]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:18]2=[O:41])=[O:16])[CH3:14])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C[C@H](N)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)C(O)C1CCCC1
Agent: Cl
Product: C[C@H](NC(=O)C(O)C1CCCC1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using cyclopentyl-α-hydroxyacetic acid (Example P) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-149° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:2). Rf=0.50 and 0.39 (CH2Cl2/EtOAc, 1:2).