Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH2:26])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].N[C:29]1C(Cl)=CC2NC(N3C=C(C(O)=O)C=N3)=NC=2[CH:30]=1.C(=O)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:14]3[CH:22]=[C:23]([Cl:27])[C:24]([NH:26][CH2:29][CH3:30])=[CH:25][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-n3cc(C(=O)O)cn3)[nH]c2cc1Cl
Reactant: CCOC(=O)c1cnn(-c2nc3cc(N)c(Cl)cc3n2COCCOC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCC=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1cc2nc(-n3cc(C(=O)OCC)cn3)n(COCCOC)c2cc1Cl
Temperature: 23 °C
Reaction time: 22 h
Yield: 54 %

Procedure:
To a solution of 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 41, product from Step A) (0.300 g, 0.762 mmol) and propionaldehyde (61.0 μL, 0.838 mmol) in THF (3 mL) was added sodium triacetoxyborohydride (0.226 g, 1.07 mmol) followed by acetic acid (40.9 μL, 0.762 mmol). The reaction mixture was stirred at 23° C. for 22 h. Molecular sieves (4 Å, 1.2 g) were added, and the reaction was kept at 40-50° C. for 24 h. Over the next 48 h, two additional portions of both propionaldehyde and sodium triacetoxyborohydride were added. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL). The aqueous layer was extracted with EtOAc (3×35 mL) and the combined organic layers were washed with brine (25 mL), dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (10-45% EtOAc/hexanes) to yield the titled compound (0.178 g, 54% yield) as a 1:1 mixture of regioisomers. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.76 (s, 1H), 8.15 (s, 2H), 7.63 (s, 1H), 7.55 (s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 6.03 (s, 4H), 4.42 (br s, 1H), 4.35 (q, J=7.1 Hz, 4H), 4.27 (br s, 1H), 3.65-3.59 (m, 4H), 3.49-3.41 (m, 4H), 3.33 (s, 3H), 3.32 (s, 3H), 3.23-3.12 (m, 4H), 1.82-1.69 (m, 4H), 1.37 (t, J=7.1 Hz, 6H), 1.11-1.01 (m, 6H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[C:14]3N)=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.[CH2:37]([N:39]=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:39][CH2:37][C:14]2[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=2)=[N:9][N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:16]=3)=[O:35])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCN=C=NC(C)(C)CC
Reactant: Nc1cccc2nn(CCN3CCCC3)cc12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)NCc1cccc2nn(CCN3CCCC3)cc12
Reaction time: 6 h

Procedure:
A 10 mL culture tube with screw cap was charged with 2-(2-pyrrolidin-1-yl-ethyl)-2H-indazol-4-ylamine (56.0 mg, 0.243 mmol), (4-benzyloxy-phenyl)-acetic acid (60.0 mg, 0.248 mmol), ethyldimethylpropylcarbodiimide hydrochloride (57.0 mg, 0.298 mmol), N-hydroxybenzotriazole (40.0 mg, 0.296 mmol), N-methyl morpholine (64.0 mg, 0.633 mmol), 2 mL of N,N-dimethylformamide and the reaction vessel placed on a shaker for 6 hours. After this time, the N,N-dimethylformamide was removed in vacuo and the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.70 (m, 4H), 2.60 (m, 4H), 3.10 (s, 2H), 3.68 (s, 2H), 4.48 (t, 2H, J=6.44), 5.09 (s, 2H), 6.97 (m, 2H), 7.12–7.45 (m, 9H), 7.51 (m, 1H), 8.49 (s, 1H), 10.03 (s, 1H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.ClC(Cl)(Cl)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:26])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:13][C:12]=1[C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)=[O:9]>CS(C)=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:27]2[C:12]3[C:11](=[CH:16][CH:15]=[C:14]([C:17](=[O:26])[C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[CH:13]=3)[NH:10][C:8](=[O:9])[N:1]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(C(=O)c2ccc(NC(=O)C(Cl)(Cl)Cl)c(C(=O)c3cccc(Cl)c3)c2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2ccc3[nH]c(=O)nc(-c4cccc(Cl)c4)c3c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 77.3 %

Procedure:
Acetic acid, ammonium salt (0.107 mol) was added at room temperature to a mixture of intermediate 12 (0.0536 mol) in DMSO (250 ml). The mixture was stirred at 60° C. for 4 hours then brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water and taken up in warm CH3CN. The precipitate was filtered, washed with diethyl ether and dried under a vacuo, yielding 16.2 g (77%) of intermediate 13. The mother layer was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH; 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (1.2 g, 6%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.9 g (4%) of 4—(3-chlorophenyl)-6-(4-methoxybenzoyl)-2(1H)quinazolinone (intermediate 13), mp. 248° C.
Reaction SMILES: [O:1]([CH2:8][CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:12](Cl)([OH:15])(=O)=[O:13].[CH4:17]>N1C=CC=CC=1>[CH3:17][S:12]([O:11][CH:9]([CH3:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])=[O:13]
Reactant: C
Reactant: O=S(=O)(O)Cl
Reactant: CC(O)COc1ccccc1
Solvent: c1ccncc1
Product: CC(COc1ccccc1)OS(C)(=O)=O
Reaction time: 48 h

Procedure:
To 1-phenoxy-2-propanol (1 mole) dissolved in pyridine (500 ml) is added methane sulfochloride (1 mole) at a rate sufficient for the temperature of the reaction mixture to reach a value of 40°-50° C., with stirring. On completion of the addition, the reactor is sealed and the reaction mixture is left aside at room temperature during 48 hours. The reaction mixture is then poured over ice. The aqueous phase is extracted with methylene chloride. The organic phase is washed with dilute sulfuric acid and then with water to neutral pH. The resulting material is dried over sodium sulfate and concentrated, to give an oil which crystallizes. The material is taken up into ether, with stirring, to give a white precipitate which is suction filtered. M.p. = 58° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23]>>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([OH:18])[CH:20]=3)[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1OCC1CCNCC1
Reactant: O=C(O)c1cccc(O)c1
Product: N#Cc1c(N)cccc1OCC1CCN(C(=O)c2cccc(O)c2)CC1

Procedure:
Prepared as in Example 24a from 2-amino-6-(piperidin-4-ylmethoxy)benzonitrile (Example 34c) and 3-hydroxybenzoic acid as an orange glass (66%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (m, 2H), 1.66-1.92 (m, 2H), 2.06 (m, 1H), 2.80 (brs, 1H), 3.05 (brs, 1H), 3.62 (brs, 1H), 3.91 (d, J=8.0 Hz, 2H), 4.49 (brs, 1H), 5.99 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 6.34 (d, J=8.0 Hz, 1H), 6.72-6.83 (m, 3H), 7.15-7.24 (m, 2H), 9.65 (s, 1H). MS 352 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17](Cl)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[O:35][CH2:36][O:37][C:30]=12>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]5[O:35][CH2:36][O:37][C:30]=45)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Nc1ccnc2c1OCO2
Reactant: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Cl)ncnc3c2)CC1
Product: CC(=O)N1CCN(CCOc2cc(OC(C)C)c3c(Nc4ccnc5c4OCO5)ncnc3c2)CC1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 16, 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-chloro-5-isopropoxyquinazoline was reacted with 4-amino-2,3-methylenedioxypyridine to give the title compound in 55% yield; NMR Spectrum: (CDCl3) 1.55 (s, 3H), 1.56 (s, 3H), 2.1 (s, 3H), 2.59 (m, 4H), 2.89 (m, 2H), 3.51 (m, 2H), 3.67 (m, 2H), 4.24 (m, 2H), 4.85 (m, 1H), 6.13 (s, 2H), 6.57 (s, 1H), 6.85 (s, 1H), 7.71 (d, 1H), 8.41 (d, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 495.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[C:22]([CH3:29])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:26][C:24]1[CH:23]=[C:22]([CH3:29])[C:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:6]=2)=[C:2]([CH3:1])[CH:25]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-nitro-phenoxy)-2-(4-fluoro-benzenesulfonyl)-phenol (11.4 grams, 27.4 mmol) in a mixture of ethanol (200 mL and ethyl acetate (200 mL) was added catalyst (10% palladium on carbon, 2.3 grams). The mixture was hydrogenated under 45 psi at room temperature for 4 hours. The mixture was filtered through Celite and concentrated to give the title compound of Step D (10.5 grams) as a tan solid. The product was used in the next step without further purification. 1H NMR (400 MHz, CD3OD) δ7.98-7.92 (m, 2H), 7.29-7.22 (m, 2H), 7.21 (d, 1H), 6.92 (dd, 1H), 6.78 (d, 1H), 1.98 (s, 6H). MS (APCI−) Calc.:387.1, Found: 386.2 (M−1).
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.C(=O)([O-])O.[Na+].Cl.ClCC([NH:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/[C:33](Cl)=[O:34])[N:31]=1)=O.Cl>C(OCC)(=O)C.O.O1CCCC1>[NH2:26][C:27]1[S:28][CH:29]=[C:30](/[C:32](=[N:36]/[O:37][CH3:38])/[C:33]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]23)=[O:34])[N:31]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: CO/N=C(\C(=O)Cl)c1csc(NC(=O)CCl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1csc(N)n1

Procedure:
In 800 ml of a mixture (1:1) of water and tetrahydrofuran (hereinafter abbreviated as "THF") was suspended 16.9 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid, to which was added, while stirring under ice-cooling, 27.72 g of sodium hydrogencarbonate. To the mixture was then added 29.4 of 2-(2-chloroacetamidothiazol-4-yl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride gradually, followed by stirring for 30 minutes. To the reaction mixture were added 150 ml of water and 200 ml of ethyl acetate, which was shaken and then left standing to form two layers. The aqueous layer was taken, to which was added, while stirring under ice-cooling, 1N HCl to adjust the pH at 7.0. To the resultant was gradually added 18.9 g of sodium N-methyl dithiocarbamate while stirring at room temperature to remove the amino-protecting group (confirming by TLC). To the reaction mixture was added 300 ml of ethyl acetate, and the mixture was shaken and then left standing to form two layers. The aqueous layer was taken and concentrated to a volume of 70 ml under reduced pressure. The concentrate was subjected to a column chromatography using XAD-II (1 l), followed by elution with water. Fractions containing the object compound were collected and concentrated to a volume of 100 ml. To the concentrate was added, while stirring under ice-cooling, 4N HCl to adjust the pH at 2.5. Precipitating crystals were collected by filtration, washed with 100 ml of water, 50 ml of ethyl acetate and 50 ml of THF, followed by drying under reduced pressure to give 19.3 g of 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:25]=1)[C:7](=[O:24])[CH:8]=[C:9]([CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12])[N:10]=2.[Br:26]Br.O>C(O)(=O)C>[Br:26][C:8]1[C:7](=[O:24])[N:6]2[CH:25]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[CH:11]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:12]
Reactant: CC(NC(=O)OCc1ccccc1)c1cc(=O)n2cc(F)ccc2n1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CC(NC(=O)OCc1ccccc1)c1nc2ccc(F)cn2c(=O)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
E1 (385 mg, 1.13 mmol) was dissolved in 14 mL of acetic acid. Bromine (58 μL, 1.13 mmol) was added dropwise. The reaction was stirred for 30 min at room temperature. Water (40 mL) was added into the reaction, and the reaction was stirred for another 30 min generating a white precipitate that was filtered, washed with water and dried to yield E2 (312 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[CH:14][C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: COCOc1ccccc1C=O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COCOc1ccccc1C=CC(=O)O
Yield: 87.8 %

Procedure:
To a solution of 2-methoxymethoxybenzaldehyde (15.0 g, 90.3 mmol) in pyridine (80 mL) were added malonic acid (18.8 g, 181 mmol) and piperidine (1.0 mL, 9.0 mmol) followed by heating to reflux for 6 hours. Water was added to the residue prepared by evaporation of the solvent therefrom in vacuo and the mixture was acidified with a diluted hydrochloric acid. The crystals separated out therefrom were filtered and washed with water to give the title compound (16.5 g, 88%).
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[CH2:17][O:16][C:14](=[O:15])[CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH3:20])[C:14](=[O:15])[CH2:13][C@@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:17][OH:16]
Reactant: CNC
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Solvent: C1CCOC1
Product: CN(C)C(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3-(S)-((carbobenzyloxy)amino)-γ-butyrolactone (prepared according to the procedure described in McGarvey, G. J.; Williams, J. M.; Hiner, R. N.; Matsubara, Y.; Oh, T. J. Am. Chem. Soc. 1986, 108, 4943-4952, 7.72 g) in THF (100 mL) was saturated with gaseous dimethylamine, stirred at room temperature for 16 hours, and concentrated. The residue was filtered through a plug of silica gel eluting with 50% acetone in hexanes to give the desired product.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH3:11][OH:12]>>[Cl:2][C:3]1[N:8]=[C:7]([O:12][CH3:11])[C:6]([F:10])=[CH:5][N:4]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CO
Agent: [Na]
Product: COc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a mixture of sodium (450 mg, 19 mmol) in methanol (20 mL) was added a solution of 2,4-dichloro-5-fluoropyrimidine (3.25 g, 19 mmol) in methanol (10 mL). The reaction mixture was stirred at room temperature overnight before being partitioned between water and diethyl ether. The organic phase was separated, washed with brine and evaporated to dryness to give the title compound as an orange oil (80%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][CH:20]([C:22](O)=[O:23])[CH3:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[CH3:1][N:2]([CH3:10])[C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:5][C:22](=[O:23])[CH:20]([CH3:21])[NH:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N(C)C
Product: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)N[C@H](C(=O)N(C)C)C(C)C

Procedure:
Following General Procedure D and using valine N,N-dimethyl amide (from Example D above) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the title compound was prepared as a solid (mp=145-160° C.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[C:12](Cl)([Cl:14])=[O:13]>C1C=CC=CC=1>[Cl:14][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: CCCCOCCOCCO
Solvent: c1ccccc1
Product: CCCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24.3 G. (150 mmoles) of 2-(2-n-butoxyethoxy)ethanol is added dropwise with stirring to 250 ml. (290 mmoles) of a 12.5% phosgene solution in benzene, cooled in an ice bath and protected from moisture. The addition is carried out over a period of approximately 1 1/2 hours and stirring is continued in an ice bath for 2 hours. The solution is allowed to warm to room temperature and stirred overnight. Nitrogen is passed through the solution for several hours to remove excess phosgene and excess HCl. The solvent is removed in vacuo affording 32.9 g. of a colorless oil. The infrared spectrum revealed a strong carbonyl absorption and no hydroxy absorption. The oil is used without any further purification in the next step.
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[NH4+:5].[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[C:27]([CH3:29])=[C:26]([CH3:30])[N:25]=[C:24](OC4C=CC=CC=4)[C:23]=3[N:22]=[C:21]2[CH2:38]CC)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]2[C:28]3[C:27]([CH3:29])=[C:26]([CH3:30])[N:25]=[C:24]([NH2:5])[C:23]=3[N:22]=[C:21]2[CH2:38][CH2:1][CH3:2])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [NH4+]
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccccc1
Reactant: CC(=O)[O-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Ammonium acetate (18 g, 0.23 mol) and 1-[5-(benzenesulfonyl)pentyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (1.74 g, 3.54 mmol) were heated at 165° C. in a sealed tube for 8 hours with stirring. Following the work-up, an analysis by NMR indicated that starting material was present; additional ammonium acetate was added (18 g, 0.23 mol), and the reaction was continued overnight at 160° C. The solution was allowed to cool to room temperature and partitioned between chloroform (100 mL) and 1 M sodium hydroxide (75 mL). Following the work-up, the crude product (1.37 g) was purified by column chromatography on silica gel (eluting with 97:3:0.1 dichloromethane:methanol:ammonium hydroxide) and then recrystallized from acetonitrile to provide 0.715 g of 1-[5-(benzenesulfonyl)pentyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine as a white powder, mp 134.0-136.0° C. with a phase change at 122-125° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].[F-:13].[K+].C1OCCOCCOCCOCCOCCOC1>CN1C(=O)CCC1.CCOC(C)=O.O>[Br:1][C:2]1[C:3]([F:13])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2[nH]cnc2c(Cl)c1Br
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nc2[nH]cnc2c(F)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-7-chloro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in NMP is added KF (3.00 equivalents) and 18-crown-6 (0.20 equivalents) at room temperature. The resulting mixture is refluxed with stirring for 16 hours. The reaction mixture is cooled to room temperature and diluted with EtOAc and water. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to afford the desired product that is purified by flash column chromatography as necessary.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:21]=1[NH2:22]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:22][C:21]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:20]=3[F:19])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cc(F)c(F)cc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cc(F)c(F)cc1F
Yield: 62.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 294 mg of 2,4,5-trifluoroaniline in place of the 2,4-difluoroaniline. 230 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-(2,4,5-trifluorophenyl)acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].[OH-].[Na+].Cl.[NH2:15]O.Cl>O.CCO>[C:6]1([C:2]2[O:1][N:5]=[C:4]([NH2:15])[CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirred solution of 3-oxo-3-phenylpropanenitrile (1.5 g, 10.3 mmol) and NaOH (452 mg, 11.3 mmol) in water (10 mL)/EtOH (10 mL) was added hydroxylamine hydrochloride (785 mg, 11.3 mmol). The mixture was stirred at 80° C. for overnight. At this point, conc. HCl (1.3 mL, 15.5 mmol) was added and the resulting mixture was heated at 80° C. for 2 h. It was then basified to pH 10 and extracted with ethyl acetate. The combined extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with ethyl acetate/petroleum ether (1:50 to 1:10) to afford 299a as a yellow solid (1.1 g, 68%). MS-ESI: [M+H]+ 161.3.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([CH:16]=[N:17][OH:18])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)[CH2:23][CH2:22][C:21]1=O.BrC(C)=C.C(N(CC)CC)C>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([Cl:15])=[C:11]([C:16]2[CH:21]=[C:22]([CH3:23])[O:18][N:17]=2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CCC(Cl)=C(C=NO)C1
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(C)Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=C(Cl)CCN(C(=O)c3ccccc3)C2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzoyl-4-chloro-3-formyl-1,2,5,6-tetrahydropyridine oxime (5,3 g, 20 mmol) in 100 ml dry dimethylformamide was added N-bromosuccinimide (4.5 g, 25 mmol) dissolved in 20 ml dry dimethylformamide. The reaction mixture was stirred at room temperature for 1 h. Now 2-bromopropene (2.2 ml, 25 mmol) and 4 ml triethylamine were added and the reaction mixture stirred at room temperature for 48 h. The compound was purified as described for 1-Benzoyl-4-chloro-3-(5-methoxymethyl-3-isoxazolyl)-1,2,5,6-tetrahydropyridine. Yield: 3.1 g. M.p. 86°-87° C.