Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9]OS(C)(=O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:15][NH:16][CH3:17]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:16]([CH3:17])[CH3:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CC1
Reactant: CNC
Solvent: C1CCOC1
Product: CCOC(=O)C1(CN(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 222 mg of 1-methanesulfonyloxymethyl-cyclopropane carboxylic acid ethyl ester in 5 mL of tetrahydrofuran was added 3 mL of 2M dimethyl amine in tetrahydrofuran, and stirred at room temperature for 3 days. The solvent was distilled off, and the residue was added with 2 mL of 1N hydrochloric acid, and washed with diethyl ether. The aqueous layer was added with 10% potassium carbonate aqueous solution, and extracted with ethyl acetate. The extracted layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 56 mg of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:16])[CH3:15]
Reactant: O=C1CCc2cc(O)cc(F)c2N1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Yield: 54 %

Procedure:
Crude 8-fluoro-6-hydroxy-3,4-dihydroquinolin-2(1H)-one (0.574 g) was treated with acetyl chloride (330 mg) and TEA (0.68 mL) in DCM (8 mL) over 3 h. After aqueous work-up with EtOAc/water, the crude product was purified with a flash column chromatography to afford the desired product (382 mg) as colorless solids.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[F:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[S:68](Cl)(=[O:70])=[O:69]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([S:68]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[F:61])(=[O:70])=[O:69])[CH2:58][CH2:59]1
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1F)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2-fluorobenzenesulphonyl chloride as the starting materials in 50% yield. LCMS for C30H32ClFN7O2S (M+H)+: m/z=608.1.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[OH:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]1.CC(=O)CC>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][OH:26])[CH2:29]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: OCC1CCCNC1
Solvent: CCC(C)=O
Solvent: O
Product: COc1ccccc1OCCCc1oc(N2CCCC(CO)C2)nc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), 3-hydroxymethylpiperidine (1.29 g) and 2-butanone (10 ml) was stirred with heating under reflux for 12 hours. The reaction mixture was poured into 100 ml of water and extracted with ethyl acetate (100 ml×2). The organic layer was washed with 100 ml of water, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography, and 4-(4-chlorophenyl)-2-(3-hydroxymethyl-1-piperidinyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole was obtained as an oil (102 mg, 27%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1.Cl.[CH3:24][CH2:25]OC(C)=O.CCCCCC>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:24][CH3:25])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1
Reactant: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)O)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)OCC)c1
Yield: 73 %

Procedure:
Acid 5a (0.583 g., 1.90 mmol, 1 equiv.) is dissolved in 12 mL of absolute EtOH. Concentrated HCl (0.6 mL) is added, and the mixture heated to reflux for 24 hours. The mixture is then partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel using 5%, then 10% EtOAc/hexane yields 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxylic acid, ethyl ester (6a) (0.432 g., 1.32 mmol, 73%) as a clear oil: UVmax (CHCl3) 242 nm (ε=12036), 296 nm (ε=4724); 1H NMR (300 MHz, CDCl3) δ 8.01 (m, 1H, ArH), 7.92 (m, 1H, ArH), 7.47-7.40 (m, 3H, ArH), 7.39 (dd, J=8, 8 Hz, 1H, ArH), 7.09 (dd, J= 2, 8 Hz, 1H, ArH), 4.34 (q, J=7 Hz, 2H, CO2CH2), 3.98 (q, J=7 Hz, 2H, CO2CH2), 3.73 (s, 3H, OCH3), 1.35 (t, J=7 Hz, 3H, CH2CH3), 0.91 (t, J=7 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 168.04 (C=O), 166.65 (C=O), 156.92, 137.28, 134.11, 133.22, 130.73, 130.07, 129.98, 128.78, 128.22, 127.63, 121.63, 113.87, 60.88, 56.02, 14.34, 13.65; IR (film) 2982, 1718, 1466, 1366, 1298, 1260, 1234, 1110, 1060 cm-1 ; MS (DCI) m/e 329 (MH+), 283 (M--C2H5O). Anal. Calcd for C19H20O5 : C, 69.50; H, 6.14. Found: C, 69.44; H, 6.19.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][N:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[C:15]2=[O:18])=[CH:10][CH:9]=1.C(OC(=O)C)C>O>[CH3:25][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[CH:9][CH:10]=2)[C:15]1=[O:18]
Reactant: Cc1ccncc1-n1ccc2ccc(N)cc2c1=O
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccncc1-n1ccc2ccc(NC(=O)C3CC3)cc2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
TEA (25.1 mL, 0.1792 mmol) and cyclopropanecarbonyl chloride (12 mL, 0.1314 mmol) were added to a solution of 7-amino-2-(4-methyl-pyridin-3-yl)-2H-isoquinolin-1-one (I-24c: 30 mg, 0.1195 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 30 minutes. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (70% ethylacetate in hexane) afforded 10 mg of the product (26.2% yield).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])(=O)=O)=CC=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CN(C=O)C>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][C@H:12]2[O:16][C@@H:15]([N:17]3[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]3=[O:19])[CH2:14][C@@H:13]2[OH:26])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)cc1
Reactant: NCc1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccc(Cl)cc3)O2)c(=O)[nH]c1=O

Procedure:
A solution of 396 mg of 5'-O-(p-toluenesulphonyl)thymidine and 1.5 ml of 4-chlorobenzylamine in 2 ml of DMF was stirred at 80° C. for 2 hours. The solvent was removed by evaporation and the residue was triturated with diethyl ether. The resulting solid was recrystallized from ethanol to yield 56 mg of 5'-(4-chlorobenzylamino)-5'-deoxythymidine, mp 179°-180° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][CH2:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[C:10]=2[C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A suspension of 1,1-dimethylethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate (13.8 g) in 1N hydrochloric acid (140 mL) was heated on a steam bath for 1.5 hours. The reaction mixture was allowed to cool to ambient temperature and then it was made basic (pH>11) with 50% sodium hydroxide. The resulting precipitate was isolated by filtration, washed with water and then dried to provide 9.5 g of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine as a white solid, m.p. 212-213° C. Analysis: Calculated for C17H24N6: % C, 65.36; % H, 7.74; % N, 26.90; Found: % C, 65.16; % H, 7.65; % N, 27.29.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 87 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(2-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.33 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]1C=CC=C[CH:18]=1.Cl>O>[C:18]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:17]
Reactant: Clc1ccc(-c2coc3ccccc23)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: N#Cc1ccc(-c2coc3ccccc23)cc1

Procedure:
A mixture of 45.2 g. (0.198 mole) of 3-(4-chlorophenyl)benzofuran, 22.2 g. (0.248 mole) of cuprous cyanide and 15 ml. of pyridine is heated to 220° C. and maintained at this temperature for one day. The mixture is then poured into a solution of 47.5 g. of ferric chloride, 30 ml. of concentrated hydrochloric acid and 135 ml. of water with stirring. The mixture is stirred with heating below its boiling point for 1 hour. The aqueous portion is removed, and the organic portion is mixed with 1.2 liter of benzene, and the mixture is stirred for 1 hour. The mixture is then filtered. The filtrate is washed with 6 N hydrochloric acid, water, 10 percent sodium hydroxide solution and saturated sodium chloride solution, then dried over magnesium sulfate. The benzene solution is then evaporated to provide a dark oil which solidifies to provide 3-(4-cyanophenyl)benzofuran. The infrared spectrum of the product is consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([CH:15]([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.P(CCCC)(CCCC)CCCC>C1COCC1>[CH3:38][C:27]1[CH:26]=[C:25]([O:21][CH:15]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:1])[F:23])=[CH:8][CH:7]=3)[N:14]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:37]=[CH:36][C:28]=1[O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCCCC(O)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A solution of 1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}-1-hexanol (131 mg, 0.41 mmol) in dry THF (15 mL) under nitrogen was cooled to 0° C. and treated with ethyl (4-hydroxy-2-methylphenoxy)acetate (85 mg, 0.41 mmol), ADDM (210 mg, 0.82 mmol) and nBu3P (204 μL, 0.82 mmol). The reaction mixture was then allowed to warm to rt slowly over 22 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc (2×30 mL) and water (30 mL). The layers were separated and the organic layer dried (Na2SO4) and reduced. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (49:1 to 24:1) afforded the title compound as a colourless oil (80 mg).
Reaction SMILES: B(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:13]([O:17]C(C)C)=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:11]2>ClCCl>[Cl:5][C:6]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[N:11]2
Reactant: CC(C)Oc1c(Cl)cc(Cl)c2ccc(-c3ccccn3)nc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: Oc1c(Cl)cc(Cl)c2ccc(-c3ccccn3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Boron trichloride (27 mL of a 1 M solution in dichloromethane, 27.6 mmol) was added dropwise to a solution of 5,7-dichloro-8-isopropoxy-2-(2-pyridyl)quinoline 15 (1.83 g, 5.51 mmol) in dichloromethane (30 mL) at 0° C. under an atmosphere of nitrogen. The mixture was stirred at 0° C. for 1 h and then allowed to warm to RT. After 24 h, some starting material was still present (by TLC analysis). More boron trichloride (14 mL) was added and stirring resumed for a further 4 h. The reaction was quenched with methanol (10 mL) and the volatiles removed in vacuo. The process was repeated until the residue reached constant weight. This gave 5,7-dichloro-8-hydroxy-2-(2-pyridyl)quinoline as the hydrochloride salt. The hydrochloride salt (1.68 g) and water (20 mL) was then treated with saturated sodium bicarbonate until the pH of the solution was 8. The mixture was the extracted with ethyl acetate (30 mL×3) and dried. The residue obtained after solvent removal was washed with methanol. This provided 5,7-dichloro-8-hydroxy-2-(2-pyridyl)quinoline (PBT 1052) as an off-white solid (1.25 g, 78%), m.p. >230° C. 1H NMR (DMSO-d6, 200 MHz): δ 10.8 (br, 1 H), 9.21 (d, J=9, 1 H), 8.30-8.62 (m, 3 H), 8.12 (m, 1 H), 7.88 (s, 1 H), 7.62 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]=[CH:10][CH3:11].[O-2].[O-2].[O-2].[Al+3].[Al+3]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:10]([CH3:11])[CH3:9]
Reactant: Cc1ccccc1N
Reactant: C=CC
Agent: [Al+3]
Agent: [O-2]
Product: Cc1ccccc1NC(C)C

Procedure:
The procedure of Example 3 was repeated using the fixed bed catalytic reactor, except that ortho toluidine or rather 2-methyl-aniline was alkylated with propylene in the presence of gamma-alumina. Table 3 below sets forth the reaction conditions and product selectivity.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[N+:22]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.CO>CO.[Pd]>[NH2:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[O:14][CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc(F)cc1N)C(=O)O
Yield: 52.4 %

Procedure:
4.35 g (S)-2-tert-Butoxycarbonylamino-3-(4-fluoro-2-nitro-phenoxy)-propionic acid in 80 ml methanol were hydrogenated with 0.14 g Pd(10%)/C. Chromatography on silicagel with dichloromethane/methanol 9:1 yielded 2.08 g (52%) (S)-3-(2-amino-4-fluoro-phenoxy)-2-tert-butoxycarbonylamino-propionic acid as light brown solid, MS m/e (%): 313.0 (M−H+, 100).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]1([C:36](Cl)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:36]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)=[O:37])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccc2ccccc12
Yield: 42 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4-phenylbutylamide (120 mg) with 1-naphthoyl chloride (71 uL) provided 66 mg (42%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14](=O)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[OH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[CH2:14][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1ccccc1O
Product: O=c1cc(N2CCN(Cc3ccccc3O)CC2)nc[nH]1

Procedure:
6-[4-(2-Hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and salicylaldehyde. Mass spectrum (ES) MH+=287.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([N:15](C(OCC(Cl)(Cl)Cl)=O)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][NH:34]1)[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:56])[C@@H:33]1[CH2:37][C:36](=[CH:38][C:39](=[O:55])[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([Cl:53])[C:41]=2[Cl:54])[CH2:35][N:34]1[C:18](=[O:20])[C@@H:16]([NH:15][C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:17])[CH3:30]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)O
Reactant: CCOC(=O)COc1ccc(C(=O)C=C2CN[C@H](C(=O)OCC)C2)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(=O)C=C2C[C@@H](C(=O)OCC)N(C(=O)[C@H](C)N[C@@H](CCc3ccccc3)C(=O)OCC)C2)c(Cl)c1Cl

Procedure:
The acid chloride from 6.7 g (14.7 mmol) of N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)-N-(2,2,2-trichloroethoxycarbonyl)alanine (Example 7A) is dissolved in 25 ml CH2Cl2 and added dropwise to a solution of 6.3 g (14.6 mmol) of 4-(2,3-dichloro-4-((ethoxycarbonyl)-methoxy)benzoyl)methylene proline ethyl ester and 1.6 g (15.8 mmol) of triethylamine in 100 ml CH2Cl2. Further reaction and purification as in example 7A gives the desired amide.
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[S:24])=[CH:18][CH:17]=1>>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[S:24])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2]
Reactant: COc1ccc(N=C=S)cc1
Reactant: COc1cc(N)ccc1NNC=O
Product: COc1ccc(NC(=S)Nc2ccc(NNC=O)c(OC)c2)cc1

Procedure:
Procedure (18.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.2g, 0.006 mole) and 4-methoxyphenyl isothiocyanate (1.1 g, 0.0066 mole). Yield 1.6 g (70%), m.p. 160°-162° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:25]=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1.CN(C)C=O>O>[CH:26]([C:27]1[CH:35]=[CH:34][C:32]([O:33][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=2[CH3:8])=[C:29]([O:30][CH3:31])[CH:28]=1)=[O:25]
Reactant: COc1cc(C=O)ccc1O
Reactant: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A mixture of methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (3.0 g), potassium carbonate (1.42 g), vanillin (1.57 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give methyl 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (3.76 g, 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 168-169° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:23](=[O:38])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)[CH:28]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:33]1([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:38])[NH:22][C:9]4[CH:10]=[C:11]([C:14]5[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:37]=[CH:36][N:35]=[CH:34]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(C#N)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(-n4ccnc4)c2)=N3)cc1

Procedure:
Prepared from {4′-cyano-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example K41) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (128 mg).
Reaction SMILES: Cl.C[O:3][C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=1)[NH2:6].[CH:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=3[N:26]=[C:25]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33]([NH:6][CH:5]([CH2:7][C:8]4[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=4)[C:4]([OH:3])=[O:17])=[O:34])=[CH:32][C:27]=3[N:26]=[C:25]2[C:36]2[CH:40]=[CH:39][O:38][CH:37]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1cc(F)c(O)c(F)c1
Agent: Cl
Product: O=C(NC(Cc1cc(F)c(O)c(F)c1)C(=O)O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
Racemic 3,5-difluorotyrosine methyl ester hydrochloride (example 119) was coupled to the carboxylic acid of example 2 in the usual manner and saponified to give the title compound of example 123.