Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[CH3:2].[CH2:21]([O:27][C:28](Cl)=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([O:27][C:28]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:18][CH:17]=2)[CH2:12][CH2:13][CH2:14]1)=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCN(CC)CCCCOc1ccc2c(c1)CCCN2
Reactant: CCCCCCOC(=O)Cl
Product: CCCCCCOC(=O)N1CCCc2cc(OCCCCN(CC)CC)ccc21

Procedure:
In analogy to example 3.9, Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and hexylchloroformate were converted to yield 6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid hexyl ester as colorless oil, MS: 405 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]([NH:16][C:17](=[O:19])[CH3:18])=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[OH-].[Na+].Cl.C>O.CO>[C:17]([NH:16][C:4](=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[C:3]([OH:20])=[O:2])(=[O:19])[CH3:18]
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NC(=Cc1c[nH]c2cc(Cl)ccc12)C(=O)O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
A 2-l. three-necked flask, equipped with thermometer mechanical stirrer and reflux condenser was charged with 90.4 g (0.31 moles) of alpha-acetamido-6-chloro-3-indoleacrylic acid methylester, 200 ml (0.40 moles) of 2N aqueous sodium hydroxide and 400 ml of methylalcohol. The mixture was stirred and heated at an internal temperature of 55-58° for 90 minutes. 800 ml of distilled water was added and the brown slightly turbid solution filtered through a Buchner funnel. The clear filtrate was acidified with 90 ml (0.54 moles) of 6N aqueous hydrochloric acid. The precipitate was collected on a Buchner funnel and washed with distilled water. The wet cake was transferred into flask and suspended in 180 ml of dimethylformamide and 600 ml of methyl alcohol. The mixture was heated on a steam bath to reflux until a brown, slightly turbid solution was formed. 6 g of charcoal was added and reflux was continued for 10 minutes. The hot mixture was quickly filtered through a bed of Celite. The deep yellow, clear filtrate was transferred into a 2-l. flask, equipped with reflux-condenser and dropping funnel and brought again to reflux under an atmosphere of nitrogen. 240 ml of distilled water was added over a 5 minute period while reflux was maintained. The mixture was allowed to stand overnight under an atmosphere of nitrogen at room temperature. The product was collected by suction filtration, washed with methyl alcohol-water 1:1 and dried at 85°/0.5 mmHg, to constant weight to give 78.6 g (86%) of product, as yellow crystals, m.p. 255°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[O:11]1
Reactant: O=Cc1ccncc1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccncc2)=CC1=O
Temperature: 60 °C
Yield: 37 %

Procedure:
To a solution of 4-pyridinecarboxaldehyde (1.4 mL, 14.9 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (2.0 g, 10.6 mM) in ethanol (50 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 323 mg, 2.1 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a red gummy product. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a white crystalline solid (1.1 g, 37% yield), m.p. 165°-166° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C:10]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH:1]1([NH:6][C:7](=[O:8])[NH:9][C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:38])([F:39])[F:40])[CH:31]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][C:66]([O:68][CH2:69][CH3:70])=[O:67])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCCCCO
Reactant: O=C(NC1CCCC1)NC(Cc1ccc(O)cc1)(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCOc1ccc(CC(NC(=O)NC2CCCC2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an oven-dried 3-necked 10 mL round-bottom flask under nitrogen was added 1-cyclopentyl-3-(2-(4-hydroxyphenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)urea, prepared as described in Procedure 11, 6, 2 and 59, (50 mg, 0.1 mmol), triphenylphosphine (34 mg, 0.1 mmol), ethyl 6-hydroxyhexanoate (17 mg, 0.1 mmol) and dry THF (0.5 mL). The reaction mixture was cooled in an ice-methanol bath and diethylazodicarboxylate (23 mg, 0.13 mmol) was added via syringe. The reaction was allowed to warm to rt and stirred overnight. The reaction mixture was concentrated in vacuo and purified by ISCO silica gel chromatography using a gradient of 5-25% EtOAc/hexanes as eluent to yield ethyl 6-(4-(2-(3-cyclopentylureido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenoxy)hexanoate (Example 313) was isolated as a white solid (43 mg, 61% yield). HPLC: RT=4.69 minutes (Phenomenex Luna C18 5μ column 4.6×50 mm eluting with 10-90% aqueous methanol containing 0.1% phosphoric acid over a 4 minute gradient monitoring at 220 nm). LC/MS [M+H] 711.3 (Phenomenex Luna C18 5μ column 4.6×30 mm eluting with 10-90% aqueous methanol containing 0.1% TFA over a 4 minute gradient monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=7.9 Hz, 2H), 7.20 (d, J=7.9 Hz, 2H), 7.12 (d, J=7.9 Hz, 2H), 7.07 (s, 2H), 6.62 (d, J=8.8 Hz, 2H), 6.56 (d, J=8.8 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 3.86t, J=6.1 Hz, 2H), 3.68 (s, 1H), 3.62 (t, J=6.6 Hz, 1H), 2.30-2.27 (m, 2H), 1.82-1.14 (m, 17H), 1.23 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[N:10]1([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3([CH2:31][N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]4)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([N:35]1[CH2:36][CH2:37][N:32]([CH2:31][C:25]2([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][N:10]4[CH2:11][CH2:12][CH2:13][CH2:14]4)=[CH:24][CH:23]=3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:33][CH2:34]1)(=[O:5])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: c1cc(C2(CN3CCNCC3)CCCCC2)ccc1OCCCN1CCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
Methanesulphonic acid anhydride (49 mg, 0.28 mmol) was added at 0° C. to a solution of 1-({1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexyl}methyl) piperazine (90 mg, 0.23 mmol) and pyridine (47 μl, 0.58 mmol) in dichloromethane (1 ml). The reaction was stirred at 0° C. for 10 minutes, then allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and partitioned between dichloromethane (20 ml) and aqueous sodium carbonate (20 ml). The layers were separated. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 by volume) to provide the title compound (61 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 1.29-1.36 (m, 3H), 1.45-1.52 (m, 5H), 1.85-1.90 (m, 4H), 2.08-2.15 (m, 4H), 2.22 (t, 4H), 2.32 (s, 2H), 2.67-2.79 (m, 9H), 3.00-3.03 (m, 4H), 4.02 (t, 2H), 6.83 (d, 2H), 7.24 (d, 2H). HRMS ESI+ m/z 464.2931 [MH]+.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:10][CH2:9][C@@H:8]([C:18]([O:20]C)=[O:19])[NH:7][C:6]1=[O:22])=[O:4].[OH-].[Na+]>CO>[C:3]([CH:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][S:10][CH2:9][C@@H:8]([C:18]([OH:20])=[O:19])[NH:7][C:6]1=[O:22])([OH:4])=[O:2]
Reactant: COC(=O)C1CCCCCCCSC[C@@H](C(=O)OC)NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCCCCCSC[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Methyl (3R)-6-methoxycarbonyl-5oxo-1-thia-4-azacyclotridecane-3-carboxylate (2.39 g, 7.21 mmol) is suspended in methanol (75 ml) and 1N sodium hydroxide (22.0 ml, 22.0 mmol) is added. The mixture is stirred for 4 hours at room temperature. The solvent is evaporated and the residue is dissolved in water (150 ml). The aqueous solution is adjusted to pH 1 by addition of 1N hydrochloric acid and extracted with ethyl acetate (3×100 ml). The combined extracts are washed with brine (1×100 ml), dried (MgSO4) and the solvent is evaporated to give (3R)-6-carboxy-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid, m.p. 167°-170° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[C:28]([O:36][CH2:37][CH3:38])[CH:27]=2)[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].CO>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:34])[CH3:35])=[C:28]([O:36][CH2:37][CH3:38])[CH:27]=2)[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)OC)ccc1OC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(Nc2ccc(C(=N)NC(=O)OCc3ccccc3)cc2)C(=O)O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To 141E (4.64 g, 8.9 mmol) in THF (20 mL) was added lithium hydroxide (17.8 mL, 1M, 17.8 mmol) then methanol (5 mL). After stirring for 2 h at rt, the reaction was concentrated and redissolved in ethyl acetate. The aqueous layer was neutralized and acidified to pH 3-4 using 10% citric acid. The product was extracted with ethyl acetate (3×) and washed with brine and dried over sodium sulfate. The solvent was removed to give 3.6 g of 2-(4-(N-(benzyloxycarbonyl)carbamimidoyl)phenylamino)-2-(3-ethoxy-4-isopropoxyphenyl)acetic acid as a yellow solid (80% yield). LC-MS: 506.11 (M+H)+. The enantiomers were separated using a semi-preparative HPLC equipped with an Astex Chirobiotic T column (20 mm×500 mm). The separation was performed using an isocratic method of methanol with 0.1% triethylamine plus 0.2% acetic acid to provide 141F.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6])#[CH:2].[CH3:10][N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17].C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:16]([C:12]2[N:11]([CH3:10])[CH:15]=[CH:14][CH:13]=2)=[O:17])[CH:7]=[CH:8][CH:9]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: Cn1cccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2cccn2C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.9 %

Procedure:
To a 0° C. solution of 3-ethynylaniline (10.35 g, 0.088 mol) in anhydrous THF (700 mL) under N2 was added dropwise 1-methylpyrrole-2-carboyl chloride (12.69 g, 0.088 mol). Triethylamine (15.0 mL, 0.108 mol) was added and the mixture was allowed to warm to rt and stirred for 16 h. The mixture was partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered and concentrated to give a brownish solid that was triturated with diethyl ether to give 13.4 g (68%) of product. LCMS (AP)+ 225.2.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH2:13][C:12]([CH2:36][C:37]#[N:38])([N:14]3[CH:18]=[C:17]([C:19]4[C:20]5[CH:27]=[CH:26][N:25](COCC[Si](C)(C)C)[C:21]=5[N:22]=[CH:23][N:24]=4)[CH:16]=[N:15]3)[CH2:11]2)[CH2:6][CH2:5]1.[F:39][C:40]([F:50])([F:49])[C:41]1[N:42]=[C:43]([C:46](O)=[O:47])[S:44][CH:45]=1>>[N:22]1[C:21]2[NH:25][CH:26]=[CH:27][C:20]=2[C:19]([C:17]2[CH:16]=[N:15][N:14]([C:12]3([CH2:36][C:37]#[N:38])[CH2:13][N:10]([CH:7]4[CH2:8][CH2:9][N:4]([C:46]([C:43]5[S:44][CH:45]=[C:41]([C:40]([F:49])([F:39])[F:50])[N:42]=5)=[O:47])[CH2:5][CH2:6]4)[CH2:11]3)[CH:18]=2)=[N:24][CH:23]=1
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: Cl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)c3nc(C(F)(F)F)cs3)CC2)C1

Procedure:
Reaction of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 4-trifluoromethylthiazol-2-ylcarboxylic acid following the procedure described for Example 1, followed by HPLC purification (method B) provided the title compound. LC-MS: 542.2 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[C:15]([OH:18])[CH:16]=2)[C:11]([C:21]2[N:29]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[CH:22]=2)=[CH:10]1>>[CH3:20][O:19][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH2:6][CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:9]([CH3:8])[CH:10]=[C:11]2[C:21]1[N:29]([S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:32])=[O:31])[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[CH:22]=1
Reactant: CC(=O)OCCBr
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCOC(C)=O

Procedure:
2-[5-Methoxy-6-(2-acetyloxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147d, but using 0.246 ml of 2-bromoethyl acetate and 0.5 g of 2-[1-methyl-5-methoxy-6-hydroxyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine. After purification by flash-pack chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents), 0.506 g of 2-[5-methoxy-6-(2-acetyloxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+].[I-].[Na+]>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 80 %

Procedure:
A mixture of 4.4 mmol of 2-(t-butyloxycarbonylamino)-3-methylpent-4-eneoic acid (2R,3S; 3S,2R) prepared by the method of P. A. Bartlett et al., J. Org. Chem., 1982, 47, 3933, in 10 ml. of dry DMF containing 4.4 mmol of benzyl bromide, 4.4 mmol of sodium bicarbonate and 10 mg. of sodium iodide was stirred for 15 minutes at 20° C. The mixture was dissolved in ethyl acetate, the solution washed three times with water, was dried over sodium sulfate, filtered and evaporated. The ester product was purified by flash chromatography on silica gel. The ester was obtained in an 80% yield as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9].C(N(CC)CC)C>C1COCC1>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccncn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccncn1
Temperature: 25 °C

Procedure:
The 4-aminopyrimidine (1.0 equiv.) was dissolved in THF and acetic anhydride (5 equiv.) and triethylamine (1.5 equiv.) were added and the mixture was stirred at room temperature. The volatiles were removed in vacuo and the residue purified by preparative silica gel TLC to give the 4-acetamidopyrimidine.
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2].CS(C)=O.[BH4-].[Na+]>C(O)(=O)C>[N+:1]([CH2:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])/C=C/c1ccc(OCc2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
To a solution of 2-(4-((E)-nitro-vinyl)-phenoxymethyl)-pyridine (33.9 g, 132 mmol) described in Manufacturing Example 203-1-2 in acetic acid (34 mL) and dimethyl sulfoxide (576 mL) was added sodium borohydride (7.99 g, 211 mmol) at room temperature while cooling appropriately. This mixture was stirred for 5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was recrystallized from heptane and ethyl acetate to obtain the title compound (6.81 g, 20%).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:29][C@@H:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](O)=[O:32])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:29][C@@H:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([NH:15][C:13]2[N:12]=[CH:11][N:10]([C:2]([CH3:9])([CH3:1])[CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:14]=2)=[O:32])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Product: CC(C)(CN1CCCC1)n1cnc(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2)c1

Procedure:
1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-4-nitro-1H-imidazole (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 496 m/z (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[N+:1]1([O-:17])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: Cc1cccnc1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 2,3-lutidine (5.00 g, 46.7 mmol) in chloroform (100 mL) at 0° C. was added m-chloroperbenzoic acid (12.0 g of a 77% max reagent) portionwise over 5 min. The reaction mixture was stirred for an additional 30 min at 0° C. and then allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated to dryness, water (20 mL) was added and the pH of the mixture was adjusted to 8 (saturated NaHCO3). The mixture was concentrated and the residue was extracted with dichloromethane/methanol (4:1). The extracts were concentrated to a white solid. Subsequent column purification (SiO2; dichloromethane/methanol, 9:1) gave 2,3-lutidine-N-oxide as a white solid (4.80 g, 83%).
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.Br[C:22]1[CH:23]=[C:24]2[N:33]([CH3:34])[CH:32]=[CH:31][C:25]2=[N:26][C:27]=1[C@@H:28]([NH2:30])[CH3:29]>O1CCOCC1>[NH2:30][C@H:28]([C:27]1[N:26]=[C:25]2[CH:31]=[CH:32][N:33]([CH3:34])[C:24]2=[CH:23][C:22]=1[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a suspension of potassium tert-butoxide (44.2 mg, 0.394 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (79 mg, 0.394 mmol) in dioxane (2 mL), was added dropwise at 90° C., a solution of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (50 mg, 0.197 mmol) in dioxane (1 mL). After 2 hours LCMS showed the reaction was complete. The volatiles were removed by nitrogen flow. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>C(OCC)(=O)C>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCc1ccccn1
Reactant: BrCCCCCBr
Solvent: CCOC(C)=O
Product: BrCCCCCOCCCc1ccccn1
Yield: 52.7 %

Procedure:
From 2-pyridinepropanol (5 g) and 1,5-dibromopentane (24.83 g), stirring the reaction mixture under nitrogen for 5 h, and using ethyl acetate for extraction. FCC eluting with cyclohexane→cyclohexane-ethyl acetate (9:1) gave the title compound as a yellow oil (5.5 g), t.l.c. (cyclohexane-ethyl acetate 9:1) Rf 0.15.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23](C(C)=C)[C:22]1=[O:33].C(=O)(O)[O-].[Na+].N>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:33])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.0 gm of 4-(3-indolyl)-piperidine, 4.0 gm of 1-(4-chloro-butyl)-3-isopropenylbenzimidazolone, 1.3 gm of sodium bicarbonate, 30 ml of dimethyl-formamide and 30 ml of tetrahydrofuran was refluxed for 16 hours. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was washed with water, dried and evaporated to dryness in vacuo. The residue was dissolved in ether, etheric hydrogen chloride was added to the solution, and the precipitate formed thereby was collected by filtration, dried and dissolved in 100 ml of ethanol. The resulting solution was cooled, 16 ml of concentrated sulfuric acid were carefully added while stirring, and the mixture was allowed to stand at 20° C. for two hours, whereupon it was poured into a mixture of ice and ammonia. The precipitate formed thereby was collected by filtration and recrystallized from ethanol, yielding 3.2 gm (55% of theory) of the compound of the formula ##STR13## having a melting point of 196° C.