Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1.[N:15]([O-:17])=[O:16].[Na+].[I-].[K+]>C(OCC)(=O)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C:8]([N+:15]([O-:17])=[O:16])=[CH:7][C:6]=2[C:5]([C:12]([NH2:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccc(F)c2c1C=CCO2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(F)c2c1C=C([N+](=O)[O-])CO2
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 66 %

Procedure:
Into a reactor, equipped with a mechanic stirrer and a reflux condenser, 8-fluoro-2H-chromene-5-carboxylic acid amide (2 g; 10 mmoles), sodium nitrite (1.4 g; 20 mmoles), potassium iodide (0.33 g; 2 mmoles) and ethyl acetate (20 ml) were charged at room temperature and under inert gas. The mixture was heated at 40° C., then Oxistrong 15® (4 ml) was added in 4 hours. At the end of the addition the reaction mixture was kept under stirring for 1.5 hours, then cooled at 20° C. and diluted with ethyl acetate up to complete dissolution (about 150 ml). After washing with a 20% sodium metabisulphite solution, the phases were separated. The organic phase was washed with a saturated sodium chloride solution, dried and the solvent was removed under reduced pressure, obtaining 8-fluoro-3-nitro-2H-chromene-5-carboxylic acid amide (1.8 g; titre 88%; 66% yield).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[O-:12][CH2:13][CH3:14].[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26]>C(O)C>[CH2:10]([O:9][C:1](=[O:8])[C:2]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])([CH2:14][CH2:13][O:12][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC[O-]
Reactant: COCCOCCOCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CCOCCOCCOC)(CCOCCOCCOC)C(=O)OCC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In an inert gas atmosphere and at room temperature, diethyl malonate (1.73 ml) is added dropwise to a solution of sodium ethoxide (0.77 g) in ethanol (25 ml). After warming at 50° C. for 1 hour, a solution of bromo-3,6,9-trioxadecane (2.6 g) in absolute ethanol (8 ml) is added and warming is prosecuted for an additional hour. A second portion of sodium ethoxide (0.77 g) is added and after additional warming for 1 hour at 50° C., the mixture is treated with an additional portion of a solution f 1-bromo-3,6,9-trioxadecane (2.6 g) in absolute ethanol (8 ml); finally, warming is prosecuted for four hours at 60° C. After removal of the solvent under vacuum, the residue is partitioned between chloroform (40 ml) and brine (10 ml). The organic phase is separated; the aqueous phase is extracted several times with chloroform. The combined organic extracts are dried and the solvent is removed under vacuum. Purification of the oily residue by column chromatography (SiO2 ; hexane/ethyl acetate 4:1 ethyl acetate) affords 2.21 g of diethyl-2,2-bis(3,6,9-trioxadecane-1-yl)malonate an uncoloured liquid. LiOH monohydrate (0.7 g) is added to aqueous solution of the ester (30 ml). The mixture is heated at 80° C. for three hours, cooled at room temperature and extracted with ethyl acetate (2×4 ml) to remove impurities. The aqueous phase is acidified at pH 1.8 with 2N H2SO4 and after NaCl addition is extracted with CHCl3. The combined chloroform extracts are dried over Na2SO4 ; removal of the solvent yields 1.4 g of 2,2-bis(3,6,9-trioxadecane- 1-yl)malonic acid, as a limpid oil. I.R. (liquid film=3600-2200 cm-1 ; 1227 cm-1 ; 1203 cm-1. By reaction of a suitable polyoxyethylenehalide with a dialkylmalonate and by final hydrolysis with lithium hydroxide the following acids:
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:7])[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:15]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:27]=1[OH:28])[C:22](O)=[O:23])([CH3:18])([CH3:17])[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:29]([C:26]1[CH:25]=[C:21]([C:22]([N:5]2[CH2:6][C:3]([OH:7])([CH3:2])[CH2:4]2)=[O:23])[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:27]=1[OH:28])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CC1(O)CNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.7 %

Procedure:
3-Methyl-azetidin-3-ol hydrochloride (0,6 g, 4,84 mmoles) was suspended in tetrahydrofuran (50 ml) and Triethylamine (1,2 ml) was added. The mixture was stirred at room temperature (approximately 25° C.) for 30 minutes and 3,5-di-tert-butyl-4-hydroxy benzoic acid (1,26 g, 5,1 mmoles) was added in one portion, the mixture was cooled to 0° C. and subsequently a solution of dicyclohexylcarbodiimide (1 g, 4,84 mmoles) in tetrahydrofuran (27 ml) was added. The reaction mixture was then heated to reflux for 3,5 hours, cooled and the insoluble solid was filtered off. The filtrate was concentrated using a rotavapor, the remaining solid dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The crude residue obtained is crystallized from diethyl ether to give 1,14 g (73% of theoretical yield) of (3,5-di-tert-butyl-4-hydroxy-phenyl)-(3-hydroxy-3-methyl-azetidin-1-yl)-methanone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:2]=1.[CH2:13]([S:17][CH2:18][C:19](O)=[O:20])[CH2:14][CH2:15][CH3:16].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:19](=[O:20])[CH2:18][S:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:2]=1
Reactant: CC(C)(C)NCc1cccnc1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSCC(=O)N(Cc1cccnc1)C(C)(C)C

Procedure:
N-[(3-pyridyl)methyl]-N-(1,1-dimethylethyl)-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 8.2 g. of N-[(3-pyridyl)methyl]-(1,1-dimethylethyl)amine with 7.4 g. of α-(n-butylthio)acetic acid and 10.3 g. of N,N'-dicyclohexylcarbodiimide in 150 ml. of dichloromethane. Weight 1.6 g. M.P. 55°-56° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][CH2:14][CH:15]([NH2:17])[CH3:16]>>[CH3:16][CH:15]([NH2:17])[CH2:14][NH:13][C:8]([NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:12]
Reactant: CCOC(=O)Nc1ccccc1
Reactant: CC(N)CN
Product: CC(N)CNC(=O)Nc1ccccc1
Temperature: 125 °C

Procedure:
A mixture of ethyl phenylcarbamate (50 g.) and 1,2-diaminopropane (105 g.) is heated at 125° C. for 17 hours and cooled, and the excess of amine is removed by evaporation under reduced pressure. The residue is dissolved in ethyl acetate and the solution is washed with saturated brine, dried and evaporated to dryness. The residue is triturated with toluene and there is thus obtained as solid residue 1-methyl-2-(3-phenylureido)ethylamine, which is used without further purification.
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([N:15]2[C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=[CH:16]2)[CH2:7]1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([N:15]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16]2)[CH2:7]1
Reactant: COC(=O)c1cncn1C1CC(C)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1CC(n2cncc2C(=O)O)c2ccccc21
Yield: 90 %

Procedure:
A solution of 3.6 parts of methyl 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-1H-imidazole-5-carboxylate mononitrate in 50 parts of a sodium hydroxide solution 20% is stirred for 1.5 hours at reflux temperature. After cooling, the reaction mixture is neutralized with acetic acid. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.4 parts (90.0%) of 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-1H-imidazole-5-carboxylic acid; mp. 209.3° C. (compound 2.36).
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH:16]([Cl:19])([Cl:18])[Cl:17].[OH-].[K+]>CN(C=O)C.CO>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)=[CH:9][CH:10]=1)[OH:13]
Reactant: ClC(Cl)Cl
Reactant: CCc1nnc(-c2ccc(C=O)cc2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nnc(-c2ccc(C(O)C(Cl)(Cl)Cl)cc2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g, 7.9 mmol) in anhydr DMF (7 mL) was added CHCl3 (2.13 g, 17.8 mmol). After cooling to −10° C., a solution of KOH (0.31 g, 5.5 mmol) in anhydr MeOH (1.5 mL) was added dropwise over 20 min. After stirring at −10° C. for 1 hr, the reaction mixture was quenched with 1 M HCl. The solid formed was collected on a Büchner, washed with H2O and dried under vacuum to give 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as a white solid (2.0 g, 80% yield).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:4].C([O-])([O-])=O.[K+].[K+].C[C:26]([N:28](C)[CH3:29])=O>C1COCC1>[C:15]([C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:28]([CH3:29])[CH3:26])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1NC(=O)CBr
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1cc([N+](=O)[O-])ccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(2-tert-butyl-5-nitro-phenyl)-acetamide (80 g, 253 mmol) and K2CO3 (70 g, 506 mmol) were combined in a 3-L 3-neck round bottom flask fitted with a mechanical stirrer, N2 inlet, and pressure equalizing addition funnel. THF (1.75 L) was added and the mixture was cooled to 0° C. under N2. DMA (400 mL of a 2 M solution in THF, 800 mmol) was added to the mixture through the pressure equalizing addition funnel over 30 min. The mixture was gradually warmed to RT with stirring overnight. The reaction was quenched by filtering it under vacuum and then concentrating the filtrate under reduced pressure. The recovered material was eluted through a 36×7 cm column of silica gel with 50% EtOAc:Hexanes giving N-(2-tert-butyl-5-nitro-phenyl)-2-dimethylamino-acetamide as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.CN([CH:31]=[O:32])C>CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH:31]=[O:32])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(C=O)cnc21
Temperature: 25 °C
Yield: 103.1 %

Procedure:
To a stirred and cooled (−78° C.) solution of the bromide 4 (5.00 g, 15.96 mmol) in Et2O (92 mL) was added dropwise 1.5 M solution of tert-butyllithium in pentane (22.3 mL, 33.5 mmol). After 45 min additional stirring at −78° C., DMF (5.6 mL, 72.3 mmol) was added dropwise, and the mixture was allowed to slowly warm to r.t. After 20 h the mixture was partitioned between saturated aqueous NaHCO3 solution and CH2Cl2. The organic layer was separated, dried (MgSO4), and concentrated to afford the crude aldehyde 13 (4.32 g). 1H NMR (400 MHz; CDCl3) δ 0.32 (s, 6H), 0.92 (s, 9H), 3.02 (m, 2H), 3.70 (m, 2H), 7.55 (d, J=2.0 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H), 9.61 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A solution of 56 mg (0.24 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 10 mg (0.24 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 74 mg (0.24 mmol) 3-Chloromethyl-5-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 56 mg (49%) of the title compound as light brown powder.
Reaction SMILES: [CH3:1]C1C=CC(Br)=CC=1.BrC1C=CC=CC=1.C(N1N2C3C4C=NNC=4N=CC=3C(=O)N(C3C=CC=CC=3)C2=CC1C)C1OC=CC=1.CC1C=C2N(C3C=CC=CC=3)C(=O)C3C=NC4NN=CC=4C=3N2N=1.[C:70]([N:78]1[C:82]2[N:83]=[CH:84][C:85]3[C:86](=[O:101])[N:87]([C:95]4[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=4)[C:88]4[N:89]([N:91]=[C:92]([CH3:94])[CH:93]=4)[C:90]=3[C:81]=2[CH:80]=[N:79]1)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>>[C:70]([N:78]1[C:82]2[N:83]=[CH:84][C:85]3[C:86](=[O:101])[N:87]([C:95]4[CH:100]=[CH:99][C:98]([CH3:1])=[CH:97][CH:96]=4)[C:88]4[N:89]([N:91]=[C:92]([CH3:94])[CH:93]=4)[C:90]=3[C:81]=2[CH:80]=[N:79]1)(=[O:77])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n2n1
Reactant: Cc1ccc(Br)cc1
Agent: CC1C=C2N(c3ccccc3)C(=O)c3cnc4[nH]ncc4c3N2N1Cc1ccco1
Agent: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Solvent: Brc1ccccc1
Product: Cc1ccc(-n2c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n3nc(C)cc23)cc1

Procedure:
By substituting p-methylphenyl bromide for the bromobenzene in the procedure of Example 21 (a), and proceeding as in parts (b) and (c), 8-benzoyl-2-methyl-4-(p-methylphenyl)-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](=[O:19])[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: C1CCNCC1
Product: O=C(NCC(=O)N1CCCCC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidine (50.0 mg, 0.59 mmol). The title compound was obtained as a solid (45.0 mg, 22% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.06 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 4.06 (2H, m), 3.38 (4H, m), 1.57 (2H, m), 1.48 (2H, m), 1.24 (2H, m). MS m/z: 475.08, 477.08 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C-:9]#[N:10].[K+].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CC#N.[Zn+2].[I-].[I-]>[Si:16]([O:8][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]#[N:10])([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cccnc1
Agent: [I-]
Agent: [K+]
Agent: [Zn+2]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OC(C#N)c1cccnc1
Yield: 93.5 %

Procedure:
To a solution of 3-pyridinecarboxaldehyde (1.0 g, 9.34 mmole) in CH3CN (45 mL) was added KCN (6.0 g, 93 mmole), TBDMSCl (1.7 g, 11.21 mmole), and ZnI2 (50 mg, 0.16 mmole). After 4 hr at RT the mixture was filtered through celite® and the filtrate was concentrated. Flash chromatography on silica gel (25% EtOAc/hexanes) gave the title compound (2.17 g. 94%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 8.63-8.73 (m, 2 H), 7.80-7.87 (m, 1 H), 7.33-7.41 (m, 1 H), 5.57 (s, 1 H), 0.97 (s, 9 H), 0.27 (s, 3 H), 0.19 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([CH2:22][OH:23])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C=C2C(C=C(C[C@H](N)C(O)=O)C=C2)=CC=1.[CH3:40][O:41][C:42]([NH:44][CH:45]([CH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1)[C:46](O)=[O:47])=[O:43].C1C=C2C=CC=C(C[C@H](N)C(O)=O)C2=CC=1>>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@H:45]([C:46](=[O:47])[NH:21][CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:22][OH:23])[CH2:49][C:50]1[CH:59]=[CH:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:51]=1
Reactant: CC(C)CN([C@H](CO)CCCCN)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)NC(Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: N[C@@H](Cc1cccc2ccccc12)C(=O)O
Product: COC(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (1S)-4-amino-N-(5-amino-1-hydroxymethyl-pentyl)-N-isobutyl-benzenesulfonamide (XII) (example 28, step D) as described in general procedure B using L-2-naphthylalanine. The L-2-naphthylalanine was initially transformed into its 2-methoxycarbonylamino-3-naphthalen-2-yl-propionic acid derivative following the procedure used for L-1-naphthylalanine (example 28, step E). The final product was obtained in 41% yield (165 mg).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(-c2oc(C)nc2C(=O)O)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-p-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:31]([O-:33])=[O:32])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].[N+](C1C=C2C(=CC=1)N=C(N1C=C(C(O)=O)C=N1)NC2=O)([O-])=O.Cl[CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62]>C1COCC1>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:31]([O-:33])=[O:32])[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C(O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)n2COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
DIEA (4.41 mL, 25.6 mmol) was added to a suspension of 1-(6-nitro-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 164, product from Step D) (4.21 g, 12.8 mmol) in THF (64 mL), followed by (2-chloromethoxy-ethyl)-trimethylsilane (2.49 mL, 14.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The residue was partitioned between water (75 mL) and EtOAc (75 mL), and the organic layer was washed with water (2×75 mL) and brine (50 mL), dried (MgSO4), and concentrated to yield the titled compound (5.92 g, 86% yield, 85% pure). This material was carried on to the next step without further purification. MS (ESI/Cl): mass calcd. for C20H25N5O6Si, 459.2; m/z found, 402.1 [M+H−58]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][OH:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O-])(=[O:21])[CH3:20].[Na+].C(Cl)(=O)C>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH2:13][CH2:14][O:15][C:19](=[O:21])[CH3:20])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[O-]
Reactant: O=C(N[C@@H](CCO)C(=O)O)OCc1ccccc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Product: CC(=O)OCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 67.1 %

Procedure:
1.27 g (5 mmol) of N-benzyloxycarbonyl-L-homoserine are dissolved in 5 ml of acetic acid, and 0.41 g (5 mmol) of sodium acetate is added. 1.19 g (15 mmol) of acetyl chloride are then added and stirring is carried out for one hour. The acetic acid and the excess acetyl chloride are removed in vacuo, the residue is taken up in 30 ml of methyl isobutyl ketone and 30 ml of water, and the pH is adjusted to 8 using 50% sodium hydroxide solution. The aqueous phase is separated off, adjusted to pH=2 using hydrochloric acid and extracted using 30 ml of methyl iso-butyl ketone. Concentration of the organic phase in vacuo yields 0.99 g (67%) of N-benzyloxycarbonyl-O-acetyl-L-homoserine in the form of a colourless oil.
Reaction SMILES: [C:1]1([N:7]2[C:12](=O)C3SC=C(C4C=CC=CC=4)C=3N=C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.[Cl:50]C1C=CC(N)=CC=1>C(O)(=O)C>[Cl:50][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:36](=[O:38])[C:25]3[S:26][CH:27]=[C:28]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[F:35])[C:24]=3[N:23]=[CH:12]2)=[CH:2][CH:3]=1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: Nc1ccc(Cl)cc1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1-c1ccc(Cl)cc1
Yield: 27 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 40 mmol), triethyl orthoformate (2.0 ml), 4-chloroaniline (94.43 mg, 0.74 mmol), and acetic acid (0.1 ml) were used to give 38 mg (0.11 mmol, 27% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]([F:12])[F:11])[C:5]#[N:6].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C]=[O:50].C[CH2:52][O:53][CH2:54]C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C.CO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]([F:12])[F:11])=[C:2]([CH:3]=1)[C:52]([O:53][CH3:54])=[O:50])#[N:6]
Reactant: CCOCC
Reactant: N#Cc1ccc(C(F)F)c(Br)c1
Reactant: [C]=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)ccc1C(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
Purge a mixture of 3-bromo-4-(difluoromethyl)benzonitrile (8.87 g, 38.2 mmol, 1.0 equiv), triethylamine (16.0 mL, 114.7 mmol, 3.0 equiv), methanol (70 mL), and DMF (120 mL) with nitrogen, then treat the mixture with palladium(II) acetate (867 mg, 3.82 mmol, 0.1 equiv) and 1,3-bis(diphenylphosphino)propane (1.61 g, 3.82 mmol, 0.1 equiv). Stir the mixture under 138 kPaG of carbon monoxide at room temperature for two days and then 80° C. for one day. Cool the mixture to room temperature and dilute with Et2O (300 mL). Wash the mixture with water and saturated aqueous NaCl, and separate the organic layer. Dry the organic layer over sodium sulfate, filter, and concentrate under reduced pressure. Subject the resulting crude material to chromatography on silica gel eluting with a 10-15% THF/hexanes gradient to give the title compound (6.19 g, 77%). GC/MS (m/z) 211 (M).