Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:9][N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 0.5 g (1.936 mmol) 4-tert-Butoxycarbonylamino-piperidine-4-carboxylic acid methyl ester, 0.387 g (2.03 mmol) p-toluenesulfonyl chloride and 0.587 g (5.8 mmol) NEt3 in 6 mL DCM was stirred at room temperature over night. DCM and NaHCO3 aq. was added and the organic layer was separated and dried with MgSO4. After evaporation the residue was dried under high vacuum and used without further purification. 0.796 g (95%) of the title compound was obtained as white foam. MS (m/e): 413.2 [(M+H)+].
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1)#[CH:22].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:22]#[C:21][C:23]2([OH:31])[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[CH:12][CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Brc1ccc(-c2ccncc2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(-c3ccncc3)nc2Cc2ccccc2)CN2CCC1CC2
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of 196 mg of 2-benzyl-3-bromo-6-(4-pyridyl)pyridine, 100 mg of 3-ethynyl-3-quinuclidinol, 70 mg of tetrakis(triphenylphosphine)palladium(0), 11 mg of cuprous iodide, 0.25 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring in an oil bath kept at 85° C. for one hour in a nitrogen atmosphere. After cooling as it was, the mixture was extracted with ethyl acetate-dilute aqueous ammonia. The organic phase was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel column chromatography and eluted with hexane/ethyl acetate (1:1) and then with methanol/ethyl acetate (20:1). After removing the solvent, the residue was recrystallized from hexane/ethyl acetate, to give 178 mg of the target compound.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25](OB(C2C=CC=CC=2)O)[CH:24]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[CH:3]=[C:2]([C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[S:6][CH:5]=3)=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(Br)c1
Reactant: OB(Oc1cccnc1)c1ccccc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by coupling 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-3-carboxamide with commercially available 3-pyridylphenylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 202). HPLC Ret time=1.97 min. LCMS [M+H]+ 378.2.
Reaction SMILES: CN(C=O)C.[CH2:6]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:7].[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CCOCC>[CH2:6]([O:8][C:9](=[O:23])[C@H:10]1[CH2:14][C@H:13]([O:15][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
12.2 Under an argon atmosphere, 120 ml of DMF are added to 28.01 g of 1-tert-butyloxycarbonyl-(2R,4S)-4-hydroxyproline ethyl ester, 30.28 g of tert-butyldimethylchlorosilane and 16.41 g of imidazole. The mixture is stirred for a further 2 hours. MTB ether is added, and the mixture is subjected to conventional work-up. The residue is chromatographed on silica gel, giving 40.4 g of 1-tert-butyloxycarbonyl-(2R,4S)-4-(tert-butyldimethylsilyl-oxy)proline ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:22])[CH2:21][CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: Cc1cnc(Cl)c(C=O)c1
Reactant: O=C1C=CCCC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)c(C(O)C2=CCCCC2=O)c1
Yield: 92 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclohexen-1-one (10.2 mmol., 1 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 92% yield (2.22 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.CN(CCN(CCN(C)C)C)C.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])N(OC)C)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C1COCC1.C(OCC)(=O)C>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([C:40](=[O:45])[C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:8][CH3:9])[C:2]=2[F:1])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: COc1ccccc1F
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 0.22 h
Yield: 125.2 %

Procedure:
To a stirred solution of 2-fluoroanisole (6.00 g, 47.6 mmol) and anhydrous THF (125 mL) at −78° C. under nitrogen was added butyllithium (35 mL of a 1.6 M solution in hexanes, 56.0 mmol). After stirring for 13 min, N,N,N′,N′,N″-Pentamethyidiethylenetriamine (12.9 mL, 61.8 mmol) was added dropwise and the reaction stirred at −78° C. After 168 min, a solution of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (16.8 g, 61.7 mmol) in anhydrous THF (40 mL) was added dropwise over 25 min. The reaction was stirred at −78° C. for 35 min and at room temperature for 65 min. The reaction was diluted with ethyl acetate (400 mL) and washed with cold 0.5 N aqueous HCl (2×200 mL), 5% aqueous potassium carbonate (200 mL), water (200 mL), and brine (200 mL) successively. The organic phase was dried over magnesium sulfate, filtered, and the solvent removed to give 20.1 g of a yellow oil. The product was chromatographed on silica gel (350 g), using a step gradient elution of 20% ethyl acetatejheptane to 30% ethyl acetate/heptane, to afford 12.0 g (75%) of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=O.[C:22]([O:29][CH3:30])(=[O:28])[CH2:23][CH2:24][C:25]([CH3:27])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:30][O:29][C:22](=[O:28])[CH2:23][C:24]1[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:25]=1[CH3:27]
Reactant: COC(=O)CCC(C)=O
Reactant: COc1cccc(CC(=O)c2c(N)sc3c2CCCC3)c1
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1Cc1cccc(OC)c1)CCCC3
Yield: 82.7 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-anisyl)methanone (0.287 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.327 g (85%) of the title compound as a yellow solid.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1>O>[N:41]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([O:21][C:22]4[C:23]([CH3:32])=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:16][CH:17]=[N:18]3)=[CH:13][C:12]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCn1ccnc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 55.3 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (52 mg), potassium carbonate (53 mg), and imidazole (26 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (31 mg, yield 81%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[CH:16]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[NH:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:24]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[NH:25][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: N=C(N)c1ccccc1OCC1CC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC3CC3)nc2n1
Yield: 54.2 %

Procedure:
In a similar manner to Example 29 reaction of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) with 2-cyclopropylmethoxybenzamidine hydrochloride (1.45 g) and triethylamine (1.30 g) in acetonitrile (50 ml) yielded a white solid (1.18 g) which was collected, dissolved in chloroform and the chloroform solution was extracted twice with 2 Normal hydrochloric acid. The chloroform solution was evaporated under reduced pressure and the residue was recrystallized from ethanol to yield the title compound, 0.52 g, m.p. 186-187° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:1]([N:5]([CH2:14][CH2:15][CH2:16][CH3:17])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])=[CH:8][C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(N)cc1F
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCCCN(CCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of N1,N1-di-n-butyl-2-fluorobenzene-1,4-diamine (1.10 g, 4.62 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (23 mL, 23 mmol, 1 M in heptane) slowly at rt. The reaction mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (798 mg, 5.08 mmol) in CH2Cl2 (10 mL). The reaction was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:2) to give the title compound as pale yellow oil (800 mg, 50%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:49](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:49])[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1
Reaction time: 2.5 h

Procedure:
Analogously to Example 40g, 40 ml of 4M HCl in dioxane are added to 1.9 g (3 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 3 ml of DMF. After 2.5 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.55 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.74; FAB MS (M+H)+ =534.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:13]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:13]=1[CH2:14][N:15]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:36](=[O:38])[CH3:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(OCCOCc2ccccc2)c(CNc2cc(F)ccc2Oc2ccccc2)c1
Solvent: c1ccncc1
Product: COc1ccc(OCCOCc2ccccc2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Yield: 79 %

Procedure:
To a solution of 5.08 g (10.7 mmol) crude 2b in 50 ml ml pyridine was added 4.37 g (42.8 mmol) acetic acid anhydride. The reaction mixture was stirred over night and poured into ice-cold ethyl acetate. The organic phase was washed with water, diluted aqueous sodium hydrogen sulfate, water and brine and were dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:8→1:4). The desired product 2c was obtained in 79% yield (4.36 g, 8.45 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+].CO.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH2:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: CCc1c(C(=O)OC)cc(Cl)cc1N(C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)cc(Cl)cc1N(C)C1CCOCC1
Temperature: 50 °C
Reaction time: 27 h
Yield: 97.6 %

Procedure:
To a solution of methyl 5-chloro-2-ethyl-3-[methyl(oxan-4-yl)amino]benzoate (334 mg, 1.07 mmol) in THF (11 ml) was added 4M NaOH (10.7 ml). The reaction mixture was stirred at 50° C. for 27 hours. MeOH (5 ml) was added to the reaction mixture and this was stirred for a further 21 hours at 50° C. The reaction mixture was acidified to pH 2-3 with 6M HCl and extracted with DCM (5×10 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give 311 mg of the title compound as an orange oil that solidified upon standing. The material was taken through the next step without further purification. LC-MS 79%, 2.01 min (3 minute LC-MS method), m/z=298.0/300.0, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.72 (d, J=2.1 Hz, 1H), 7.37-7.27 (m, 1H), 4.00 (brd, J=11.1 Hz, 2H), 3.36 (td, J=11.6, 2.0 Hz, 2H), 3.11 (q, J=7.4 Hz, 2H), 2.94 (t, J=10.6 Hz, 1H), 2.64 (s, 3H), 1.78-1.56 (m, 4H), 1.15 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([O:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:13]=[CH:14][C:15]=2[C@@H:19]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>CO.[Pd]>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:21]([CH2:20][C@@H:19]([C:15]2[CH:14]=[CH:13][C:12]([O:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[C:11]3[C:16]=2[CH:17]=[CH:18][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:10]3)[O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:41][CH:42]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Oc1ccc2c([C@H](CN(CCCCCCOCCCCc3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)ccc(OC(=O)OC(C)(C)C)c2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1ccc2c([C@H](CN(CCCCCCOCCCCc3ccc(N)cc3)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)ccc(OC(=O)OC(C)(C)C)c2n1

Procedure:
Intermediate 41 (175 mg, 0.19 mmol) was dissolved in methanol (4 mL) and ethyl acetate (1 mL) and treated with palladium on carbon (10% w/w, wet Degussa-type, catalytic amount). The suspension was stirred under a balloon of hydrogen gas for 45 minutes. The mixture was then filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to provide the title material. ES/MS calcd. for C48H76N3O10Si+882.5. found m/z=882.5 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](Cl)=[O:19]>>[C:1]([C:5]1[C:6]([NH:14][C:18](=[O:19])[CH2:17][C:16]([CH3:22])([CH3:21])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)CC(=O)Nc1nn2cccnc2c1C(C)(C)C

Procedure:
The product from Example 105B and 3,3-dimethylbutanoyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.05 (s, 9H), 1.45 (s, 9H), 2.20 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 8.47 (dd, J=4.1, 1.7 Hz, 1H), 8.94 (dd, J=7.0, 1.9 Hz, 1H), 9.59 (br s, 1H); MS (DCI) m/z 289 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].CCCCC=CCCC>C(O)(C)C>[N+:8]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)([O-:10])=[O:9]
Reactant: O=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC=CCCCC
Solvent: CC(C)O
Product: O=C1CCCC(C[N+](=O)[O-])C1
Yield: 100 %

Procedure:
21.9 g of cyclohexanone are left to stand together with 175 ml of nitromethane and 2.1 g of 5-diazabicyclo-[4.3.0.]non-5-ene (DBN) in 250 ml of isopropanol at room temperature for 2 days. The working up is carried out in analogy to the procedure for Example 1 and provides 37.2 g (100% of theory) of 3-(nitromethyl)cyclohexanone which is pure enough for the next reaction.
Reaction SMILES: [O:1]1[CH2:14][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.[CH3:15][NH:16][CH3:17]>CO.CN(C=O)C>[OH:1][CH:2]([CH2:14][N:16]([CH3:17])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Reactant: CNC
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
4-(2,3-Epoxypropoxy)nitrobenzene (obtained as described in Synthetic Communications, 1994, 24, 833; 4.3 g,) was dissolved in methanol (30 ml) and DMF (10 ml). A solution of dimethylamine in methanol (2M, 17 ml) was added and the mixture was stirred overnight. Volatile material was removed by evaporation and the residue was partitioned between saturated sodium bicarbonate (100 ml) and ethyl acetate (100 ml). The organic layer was separated and washed with saturated sodium chloride (2×100 ml) and dried (MgSO4). Concentration gave the product as an oil that slowly crystallised under high vacuum (4.79 g, 89.9%). NMR (CDCl3): 2.33 (s, 6H), 2.98 (m, 1H), 2.54 (m, 1H), 4.00 (m, 3H), 7.00 (d, 2H), 8.20 (d, 2H); MS (M+H)+: 241.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH2:20][C:21](OC)=[O:22])=[C:14]([CH3:26])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[C:14]([CH3:26])[CH:13]=1
Reactant: COC(=O)CC(=O)Cc1ccc(F)cc1C
Reactant: N#Cc1ccnc(NN)c1
Product: Cc1cc(F)ccc1Cc1cc(O)n(-c2cc(C#N)ccn2)n1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(4-fluoro-2-methylphenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1)[NH2:6].ClCCl.C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:2][O:3][C:4](=[O:17])[C@H:5]([NH:6][C:29](=[O:30])[CH2:28][Cl:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([O:15][CH3:16])[CH:9]=1
Reactant: COC(=O)[C@H](N)Cc1ccc(C)c(OC)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc(C)c(OC)c1)NC(=O)CCl
Reaction time: 0.5 h

Procedure:
To a mixture of 3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.60 g) in a mixed solvent of dichloromethane (7 ml) and water (9 ml) was added potassium carbonate (1.70 g) in small portions under ice cooling. Chloroacetyl chloride (0.66 ml) was added to the mixture at 5° C. or below over 15 minutes and then the total mixture was stirred for 30 minutes. The organic layer was separated, washed with an aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give (2R)-2-[N-(chloroacetyl)amino]-3-(3-methoxy-4-methylphenyl)propionic acid methyl ester in the form of an oily substance.