Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37].N1C2C(=CC=CC=2)C2(COC3C=C4C(=CC2=3)CCO4)C1=O>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: BrCc1ccccn1
Agent: BrCC1CCCCO1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.[C:26](Cl)(=[O:30])[O:27][CH2:28][CH3:29]>>[C:26](=[O:30])([O:27][CH2:28][CH3:29])[O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:5]=4[C:6]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: CCOC(=O)Oc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl ethyl carbonate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 138, but using ethyl carbonochloridate. LRMS [M+H]=402.2
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: [C-]#N
Reactant: Clc1cc(Cl)c(Cl)c(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCc1cc(Cl)cc(Cl)c1Cl
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
A solution of 19.2 grams (0.070 mole) of 2,3,5-trichlorophenylmethyl bromide in 50 mL of methanol was stirred, and a solution of 4.1 grams (0.084 mole) of sodium cyanide in 10 mL of water was added dropwise during a 10 minute period. The addition caused an exothermic reaction which raised the reaction mixture temperature to about 35° C. Upon completion of the addition the reaction mixture was warmed to reflux, where it was stirred for 4.5 hours. The reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 60 hours. After this time the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of water, two 25 mL portions of aqueous 10% hydrochloric acid, and then with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.8 grams of 2,3,5-trichlorophenylacetonitrile. The infrared spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]([CH3:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:18](=[O:29])[N:17]2[CH2:30][CH2:31][CH3:32])=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH3:40][C:5]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[C:18](=[O:29])[N:17]2[CH2:30][CH2:31][CH3:32])=[CH:11][CH:12]=1)[C:4]([OH:41])=[O:3]
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Yield: 96.8 %

Procedure:
A solution of 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.456 g, 0.816 mmol) in ethanol (20 mL) is treated with aqueous 5 N NaOH (2 mL) and heated to reflux 1 h. The reaction mixture is cooled, the solvent removed. The resultant residue is acidified and extracted with CH2Cl2. The organic layer is dried and the solvent removed to afford 0.419 g (97%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid. 1H NMR. HRMS (ES+) m/z exact mass calc'd for C32H39N2O5 (M+1) 531.2859. Found m/z 531.2866.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:59]C1C=CC(C(Cl)=O)=CC=1>>[Cl:59][C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:14][CH:15]=2)=[O:8])=[CH:7][CH:6]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 113 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-chlorobenzoyl chloride. The compound of example 113 was used directly without isolation for the preparation of compound of example 114.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:12]=[C:11]([C:13]3[C:14]([C:22]4[N:23]=[C:24]([CH3:27])[S:25][CH:26]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:34]>O1CCCC1>[Cl:34][C:21]1[N:16]2[N:15]=[C:14]([C:22]3[N:23]=[C:24]([CH3:27])[S:25][CH:26]=3)[C:13]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:12]=3)=[C:17]2[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1nc(-c2nn3ccccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)c2)cs1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of N-cyclopentyl-4-[2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine (138 mg, 0.37 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. n-Butyl lithium (1.6M in hexanes, 0.75 mL, 1.22 mmol) was added dropwise. After stirring at −78° C. for 20 minutes, carbon tetrachloride (1 mL) was added to the solution. The reaction was stirred for another 20 minutes at −78° C. and subsequently quenched with water. The reaction mixture was warmed to room temperature and extracted with ethyl acetate. The organics were combined and washed with water, brine and dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (1:19 methanol/dichloromethane) gave 4-[7-chloro-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine as a brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11](O)=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:11](=[O:12])[C:10]2[CH:9]=[C:8]([O:7][C:6]3[CH:26]=[CH:27][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:14]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 75.6 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 0.45 g (1.26 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.23 g, 1.26 mmol) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.40 (9H, sm), 3.35 (6H, m), 3.55 (2H, m) 7.02 (2H, d), 7.08 (1H, t), 7.26 (2H, d), 7.88 (2H, d).
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[CH:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=1[F:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:14][CH:5]1[CH2:4][C@@H:3]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:23]=2[F:30])[C@@H:2]([CH3:1])[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6]1=[O:13]
Reactant: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)CC(NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@@H]1[C@H](c2cc(F)cc(F)c2F)CC(N)C(=O)N1CC(F)(F)F
Temperature: 5 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
To a solution of 47 (2.0 g, 4.5 mmol) in IPAC (20 mL) was added p-toluenesulfonic acid monohydrate (1.3 g, 6.8 mmol). The mixture was aged at 55° C. for 4 h. After the reaction was complete, the slurry was cooled in an ice bath to 5° C. and a solution of potassium carbonate (1.9 g, 13.6 mmol) in H2O (10 mL) was added. The aqueous layer (pH=10) was separated and the organic layer was washed with saturated aqueous NaHCO3, water and brine, in turns, and dried over Na2SO4. Concentration afforded 48 (1.3 g, 86% yield) as a 4:1 mixture of diastereomers.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][CH2:7][CH:8]=[C:9]([F:15])[C:10]([O:13][CH3:14])(F)F>CCCCC>[Br:6][CH2:7]/[CH:8]=[C:9](\[F:15])/[C:10]([O:13][CH3:14])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: COC(F)(F)C(F)=CCBr
Solvent: CCCCC
Product: COC(=O)/C(F)=C/CBr
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.4 %

Procedure:
To a mixture of 3.0 g 75% sulfuric acid and 15 mL n-pentane was added 1.0 g (4.6 mmol) 4-bromo-1-methoxy-1,1,2-trifluoro-2-butene at room temperature in a 50 mL round-bottom flask. The resulting mixture was stirred for 48 hours at room temperature. Excess ice water was added and the liquid extracted with diethyl ether. The ether layer was successively washed with water and brine, then dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo gave the crude ester which was purified by chromatography on silica gel to give 0.62 g (68.9%) of methyl (Z)-4-bromo-2-fluoro-2-butenoate. Analytical sample distilled a 90°-92° C. (18 mm Hg). 1H-NMR (300 MHz, CDCl3) δ 3.84(3H, s), 4.40(2H, dd, J=2.5, 9 Hz), 6.35(1H, dt, J=9, 30 Hz). 19F-NMR (CDCl3): φ 122.5(d, J=30.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH2:11])[N:10]=1)=[O:5])[CH3:2].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([NH:11][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:25])[F:26])=[CH:17][CH:18]=2)=[O:24])[N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(N)cn1C
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)cn1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.22 g (3.61 mmol) of 4-amino-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester (synthesis analogous to Example 1A, Stage 3, or else according to Tetrahedron Lett. 2003, 44, 1607 and literature cited there) is mixed in 50 ml of THF under argon with 1.46 g (7.21 mmol) of 4-(trifluoromethoxy)phenylisocyanate and stirred overnight at room temperature. The reaction mixture is filtered, the filtrate is concentrated by evaporation in a vacuum, and it is purified chromatographically.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH3:8])[NH:6][CH3:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH3:8])[N:6]([C:10](=[O:12])[CH3:11])[CH3:7]
Reactant: CN[C@@H](C)C(=O)OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)N(C)C(C)=O
Reaction time: 24 h

Procedure:
In 300 ml of chloroform was dissolved 33.7g (0.22 mol) of N-methyl-L-alanine methyl ester hydrochloride, followed by addition of 65 ml of acetic anhydride and 110 ml of triethylamine. The mixture was allowed to stand at room temperature for 24 hours and, after the excess acetic anhydride was decomposed with water, the solution was neutralized with sodium bicarbonate. The chloroform layer was separated and the water layer was extracted with ethyl acetate (120 ml × 5). The chloroform and ethyl acetate layers were combined and concentrated under reduced pressure. The brown-colored oily residue was dissolved in chloroform and washed with an aqueous solution of sodium hydrogen carbonate, followed by concentration under reduced pressure. By the above procedure was obtained 31.8 g of N-acetyl-N-methyl-L-alanine methyl ester.
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH2:14][C:15]([OH:17])=O>C(O)C>[N:2]1[NH:3][C:15](=[O:17])[CH2:14][CH:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=12
Reactant: NN
Reactant: O=C(O)CC1Cc2ccccc2C1=O
Solvent: CCO
Solvent: O
Product: O=C1CC2Cc3ccccc3C2=NN1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 0.53 g (0.011 mol) of hydrazine hydrate dissolved in 25 mL ethanol was added 1.2 g (0.0089 mol) of the product from step B. The reaction mixture was refluxed for 18 hours, cooled to room temperature, concentrated under vacuum, added 100 mL H2O and extracted with ethyl acetate (3×50 mL), washed with brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 1.0 g of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7]>CCO.C1COCC1.[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(N)c(OC)c1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A stirred mixture of methyl 3-methoxy-4-nitrobenzoate (1.20 g, 5.7 mmol) and 5% Pd-C (1.0 g) in EtOH (30 mL) and THF (20 mL) was hydrogenated overnight at 1 atm. The mixture was filtered and the filtrate was evaporated. The residue was chromatographed on silica-gel with CHCl3 as eluent, and the solid obtained was further purified by recrystallization from CHCl3-n-hexane to give 805 mg (78%) methyl 4-amino-3-methoxybenzoate as white plates. mp 126-128; IR (KBr) 3475, 1700 cm−1; 1H-NMR (CDCl3) δ3.86 (3H, s), 3.89 (3H, s), 4.21 (2H, br s), 6.66 (1H, d, J=8.3 Hz), 7.45 (1H, d, J=1.9 Hz), 7.54 (1H, dd, J=1.9 and 8.3 Hz); MS (FAB) m/z 182 (M++1); Anal. Calcd. for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C, 59.65; H, 6.15; N, 7.65.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=O)=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(Cl)CCl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:24])=[CH:25][CH:26]=3)=[N:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCCl
Product: CCCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1

Procedure:
4.2 g. of 4-[5-(4-n-pentylphenyl)-2-pyrimidyl]-benzoic acid amide are reacted under reflux in a mixture of 200 ml. of ethylene chloride and 2.5 ml. of phosphorus oxychloride for 1 hour, with stirring. The reaction mixture is diluted with ether and washed with 2N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, which has been dried over sodium sulfate, 5-(4-n-pentylphenyl)-2-(4-cyanophenyl)-pyrimidine is obtained and is filtered on a short silica gel column and subsequently recrystallized from methylene chloride/methanol, m.p. 125.5°; cl.p. 242.5°-243°.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3nnn[nH]3)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2cc(-c3nnn[nH]3)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-(1H-tetrazol-5-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5][CH2:4]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:9][N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87.7 %

Procedure:
A solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.94 g, 9.0 mmol) in THF (15.0 mL) was added drop-wise to a 1M solution of LiAlH4 in THF (13.5 mL, 13.5 mmol) under argon. The reaction mixture was stirred at room temperature for 17 hours and then cooled to 0° C. A mixture of THF and water (1:1 ratio, 1.5 mL) was added drop-wise. A gelatinous white solid formed. 4M aq NaOH solution (0.6 mL) was added drop-wise. Water (2 mL) was added and the resulting mixture stirred at room temperature for 2 hours. The white solid was removed by filtration. The filtrate was loaded onto an Isolute HM-N liquid-liquid extraction column and then eluted with EtOAc (200 mL). The resulting organic phase concentrated in vacuo yielding (1-methylpiperidin-4-yl)methanol as a yellow oil (1.02 g, 88%).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].O.C(N(CC)CC)C.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([NH:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:28])=[O:29]
Reactant: CC(C)[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](NS(=O)(=O)c1ccc2ccccc2c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a 12-L 3-neck flask with a mechanical stirrer, an addition funnel, and a thermometer were added 400 g (3.414 mol) of D-valine (36.0), 3 L of water, 380 mL of THF, and 1190 mL (8.572 mol) of triethylamine (TEA). To this solution was added dropwise at 5°-10° C. a solution of 774 g (3.414 mol) of 2-naphthalenesulfonyi chloride (35.0) in 800 mL THF. The mixture was allowed to warm to room temperature and stirred for 2 hours. Evaporation of THF followed by quenching into 4 L of 3 N HCl precipitated crude product. Crystallization of the crude product from t-butyl methyl ether gave 910 g (87%) of 18.1. M.p: 170°-172° C. (literature gives the m.p. as 170°-172° C.-see Kiyooka, S.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem., 1991, 56, 2276.). The spectrum data are identical to that of the literature.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH2:10])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[C:26](Cl)=[N:27][C:28]([Cl:31])=[N:29][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[NH:10][C:26]1[C:25]([Cl:24])=[CH:30][N:29]=[C:28]([Cl:31])[N:27]=1)=[O:4]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COC(=O)c1sc(-c2ccccc2)c(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)c(C)c1Nc1nc(Cl)ncc1Cl
Yield: 2 %

Procedure:
A solution of 3-amino-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.25 g, 5.06 mmol), potassium carbonate (0.7 g, 5.06 mmol) and trichloropyrimidine (2.78 g, 15.2 mmol) was heated at 50° C. in DMF (10 mL) for 16 hours. The mixture was diluted with ethyl acetate, washed with brine and water, and dried over sodium sulfate. Evaporation of solvent and column chromatography (hexane and ethyl acetate (9:1)) gave 39 mg of 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methyl-5-phenyl-thiophene-2-carboxylic acid methyl ester in 2% yield: 1H NMR (300 MHz, CDCl3) δ 8.58 (s, 1H), 7.5 (m, 5H), 3.82 (s, 3H), 2.37 (s, 3H); MS (m/e): 393.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([OH:20])=[O:19])[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36](Cl)(=[O:38])=[O:37])([O-:29])=[O:28].[CH:40]1([NH:46][CH:47]2[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>[OH-].[Na+].C(OCC)C>[CH:47]1([NH:46][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]1.[N+:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH:17][C@H:16]([C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])(=[O:38])=[O:37])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(NCCCC[C@H](NS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Yield: 82.3 %

Procedure:
Nε -benzyloxycarbonyl-L-lysine (4.42 g, 16 mmole) was dissolved in 1N aqueous sodium hydroxide (16 ml), and dioxane (10 ml) solution of o-nitrobenzene sulfonyl chloride (3.50 g, 16 mmole) was added dropwise to the solution while keeping the pH value thereof to between 10 and 11 with 1N aqueous sodium hydroxide while cooling with ice and stirring. The mixture was further stirred for 2.5 hours at room temperature, and insoluble matter was removed by filtration. The filtrate thus obtained was washed with two 100 ml portions of diethyl ether. To the water layer, ethyl acetate (150 ml) was added and the solution was adjusted to pH 1.0 with 1N aqueous hydrochloric acid under vigorous stirring. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the oily residue thus obtained was dissolved in diethyl ether (50 ml). To the solution, with stirring, dicyclohexylamine 2.99 g, 17 mmole) was added to obtain Nα -o-nitrobenzenesulfonyl-Nε -benzyloxycarbonyl-L-lysine dicyclohexylamine salt (yield:8.52 g; 83.4%)