Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][OH:5].C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>ClCCl.O>[OH:5][CH2:4][C:3]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCC(CO)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(CO)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 23 °C
Yield: 47.5 %

Procedure:
A solution of 3-amino-2,2-diphenylpropan-1-ol (18.4 g, 80.95 mmol) in dichloromethane (250 mL) was treated with triethylamine (16.9 mL, 121.4 mmol) and benzyl chloroformate (12.7 mL, 89.0 mmol) was then added dropwise over a period of 15 minutes. The reaction was stirred at 23° C., then diluted with water and stirred for 15 more minutes. The phases were separated and the organic phase was washed with 1N HCl, dried over anhydrous magnesium sulfate, filtered and concentrated to give the crude title material as an oil. This was purified on silica gel column (20% ethyl acetate/hexane) to give the title material (13.9 g, 47%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm: 2.29 (1H, br s), 4.08 (2H, d, J=6.57 Hz), 4.20 (2H, s), 4.82 (1H, t, J=6.06 Hz), 5.12 (2H, s), 7.14-7.21 (4H, m), 7.23-7.29 (2H, m), 7.31-7.41 (9H, M). HPLC ret. time (Condition C): 6.098 min. LC/MS (M+H)+: 362.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[O:10]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11]1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([C:12]2[CH:13]=[CH:14][O:10][CH:11]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Br)c1
Reactant: O=C(Cl)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(Br)c1)c1ccoc1

Procedure:
3-Bromo-4-chloroaniline (150 mg), 3-furoylchloride (0.15 ml) and sodium carbonate (1 g) were stirred for 18 hours at room temperature in DCM (15 ml). The reaction was filtered, the residue washed with DCM and the combined DCM fractions reduced to dryness under vacuum to give N-(3-bromo-4-chlorophenyl)-3-furamide. NMR; δH [2H6]—DMSO 10.13,(1H, s), 8.38,(1H, s), 8.20,(1H, d), 7.81,(1H, m), 7.73,(1H, dd), 7.59,(1H, d), 6.97,(1H, m).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12](=[N:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:13]([O:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[CH3:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:25])[C:18]=1[N:17]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH2:11])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C(C)=Nc1c(C)cccc1C
Solvent: Cc1ccccc1
Product: C=C(C(=O)OC)N(C(=O)Cc1ccccc1)c1c(C)cccc1C

Procedure:
4.35 ml of phenylacetyl-chloride (0.033 mol) were added dropwise and at room temperature to a solution of 6.7 g (0.03 mol) of N-(methyl-methoxycarbonyl-methylene)-2,6-dimethyl aniline (prepared as described in example 12 and pure at 92%) in toluene (100 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([O:28][C:32]5[N:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NC1CCCCC(Oc2ncccn2)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
As described for example 138, 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide, NaH, and 2-chloropyrimidine are reacted to give the product after flash chromatography with CH2Cl2-MeOH. LC-MS: 481 (M++1). 1H NMR (CDCl3) δ 8.75 (d, 1H), 8.50 (d, 2H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 6.92 (t, 1H), 6.85 (d, 1H), 5.55 (m, 1H), 5.15 (m, 1H), 4.10 (m, 1H), 3.70 (m, 4H), 3.23 (m, 4H), 1.80–2.25 (m, 7H), 1.50–1.70 (m, 3H).
Reaction SMILES: COC([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:11]=2)[CH2:6]1)=O.Cl>CCO>[NH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[CH2:6]1
Reactant: COC(=O)N1CCC(c2cccc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)c2)C1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(Nc1cccc(C2CCNC2)c1)c1ccc(OC(F)(F)F)cc1
Yield: 45.8 %

Procedure:
3-[3-(4-Trifluoromethoxy-benzenesulfonylamino)-phenyl]-pyrrolidine-1-carboxylic acid methyl ester (500 mg, 1.13 mmol) and HCl (8M, 137.82 mmol) in EtOH (10 ml) were heated under reflux for 48 h. The mixture was extracted twice with ethyl acetate and then NaOH (2M) was added. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water and saturated sodium chloride solution, dried over MgSO4 and evaporated under reduced pressure to give the product as a brown oil (200 mg, 46%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1O>>[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:10]
Reactant: Oc1ccccc1F
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccccc3F)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and o-fluorophenol, to afford 510 mg of the title compound as a powder.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:9](O)[N:8]=[N:7][C:5]=2[CH:6]=1.CN([P+]([O:21]N1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>>[OH:21][C:6]1[C:5]2[N:7]=[N:8][NH:9][C:4]=2[CH:3]=[CH:2][CH:1]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Oc1cccc2[nH]nnc12

Procedure:
Competition experiments demonstrate that under the reaction conditions followed the BOP Reagent functions to form the symmetrical acid anhydride within about one minute. During the remaining ten minutes of preactivation mixing a portion of the symmetrical anhydride is converted by HOBt liberated from the BOP Reagent to form an intermediate hydroxybenzotriazole active ester. This active ester intermediate then couples with the available reactive functionalities on the synthesis resin or the coupled amino acid in the peptide chain.
Reaction SMILES: Cl.[NH2:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:11][CH:12]=1)[CH2:4][OH:5].O.C(=O)([O-])O.[K+].Cl[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33]>C(OCC)(=O)C>[CH2:35]([O:34][C:32]([NH:2][C@:3]([CH3:24])([CH2:6][CH2:7][C:8]1[O:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:11][CH:12]=1)[CH2:4][OH:5])=[O:33])[CH:36]=[CH2:37]
Reactant: C=CCOC(=O)Cl
Reactant: C[C@](N)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N[C@@](C)(CO)CCc1ccc(C#CCCOC2CCCCC2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a suspension of (2R)-2-amino-2-methyl-4-[5-(4-cyclohexyloxybut-1-ynyl)furan-2-yl]butan-1-ol (0.5305 g, 1.66 mmol) obtained in Example 20 in a mixed solvent of ethyl acetate (16 ml) and water (16 ml) were added potassium hydrogencarbonate (0.1995 g, 1.99 mmol) first and then allyl chloroformate (0.21 ml, 1.98 mmol) with stirring, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, the reaction mixture was diluted with ethyl acetate and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo to afford the title compound (0.6202 g, yield: 93%)
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C:22]2([O:30][CH3:31])[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:17]=[C:18]([C:22]4([O:30][CH3:31])[CH2:27][CH2:26][O:25][C:24]([CH3:28])([CH3:29])[CH2:23]4)[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: COC1(c2cccc(O)c2)CCOC(C)(C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOC(C)(C)C1
Yield: 83 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with 4-(3-hydroxyphenyl)-4-methoxy-2,2-dimethyltetrahydropyran to give 4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2,2-dimethyltetrahydropyran in 83% yield.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:12]1(=[O:22])[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:22])=[CH:10][CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)Cc1ccccc1
Product: CC(C)(C)Cc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
In the novel process, neopentylbenzene (1) is acylated in a first step with phthalic anhydride (2) under Friedel-Crafts conditions to give 2-(4-neopentylbenzoyl)-benzoic acid (3). ##STR3##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(Br)cc1
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1ccc(Br)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-bromophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>[Cl-].[Cl-].[Zn+2]>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 180 °C
Yield: 29 %

Procedure:
To p-fluorobenzoyl chloride (49.7 g, 314 mmol), heated to 120° C., was added p-chloroaniline (17.8 g, 139 mmol) over 10 min. The mixture was then heated to 180° C. and ZnCl2 (23.8 g, 174 mmol) was added over 10 min. The resulting mixture was heated at 205° C. for 2 h. After cooling to 120° C., 3N HCl (125 mL) was added cautiously and the mixture was maintained at 120° C. for 1 h. The hot aqueous portion was then decanted and the remaining residue was washed with hot 3N HCl (2×125 mL). The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 3N HCl (2×50 mL), 5N NaOH (2×50 mL) and H2O (3×50 mL) and were then dried over MgSO4, filtered and concentrated in vacuo to provide 15 g (29%) of the N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide as a dark yellow powder. To a flask containing the acylated amino-benzophenone (6.7 g, 18 mmol) was added 1:1 conc. HCl:AcOH (700 mL) and the resulting mixture was heated to 105° C. and stirred for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 5N NaOH (2×50 mL) and H2O (3×50 mL) and then dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and recrystallized from hexanes to provide 1t (3.4 g, 76%) MS m/z=250 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13](=[O:15])(=[O:14])[NH:12][C:11](=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[O:17]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([SiH](CC)CC)C>Cl.O1CCOCC1>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[S:13](=[O:15])(=[O:14])[NH:12][C:11](=[O:16])[CH:10]=3)=[CH:7][CH:8]=2)=[CH:30][CH:31]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C=C(c2ccc(CO)cc2)S(=O)(=O)N1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C=C(c2ccc(COCc3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Reaction time: 21 h
Yield: 5 %

Procedure:
5-[4-(Hydroxymethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (80 mg, 0.33 mmol) was suspended in 4 M hydrogen chloride in 1,4-dioxane (2.0 mL). 4-Phenoxybenzaldehyde (0.080 mL, 0.46 mmol) was added, followed 15 minutes later by triethylsilane (0.075 mL, 0.47 mmol). After stirring for 21 h, additional triethylsilane (0.050 mL, 0.31 mmol) was added, followed 3.5 h later by 4 M hydrogen chloride in 1,4-dioxane (1.0 mL, 4 mmol). The product was purified on a 50 mm Luna C18 column using a 20–100% acetonitrile in water gradient with 0.05% trifluoroacetic acid at 30 mL per minute over a 30 minute period. The product was lyophilized to give a white powder (7 mg, 5%). 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.34 (m, 4H), 7.11 (t, J=1.2 Hz, 1H), 7.01 (m, 4H), 6.71 (s, 1H), 4.63 (s, 2H), 4.56 (s, 2H); LCMS found for C23H19NNaO5S (M+Na)+: m/z=444.0.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][OH:27])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[H-].[Na+].[CH3:31]I>C1COCC1>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH2:26][O:27][CH3:31])[C:20]4=[N:19][C:18]=3[CH3:28])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(CO)cccn34)c(C)nc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(COC)cccn34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
A solution of {3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridin-8-yl}-methanol (0.23 g, 0.60 mmol) in THF (10 mL) is treated with 60% NaH (29 mg, 0.73 mmol) at 0° C., and the resulting mixture is stirred at 0° C. for 30 min. CH3I (56 μL, 0.91 mmol) is added and the reaction is stirred at 0° C. for 2 h, and at RT overnight. It is quenched with sat. NH4Cl (10 mL), diluted with H2O (20 mL), and extracted with EtOAc (2×20 ml). The combined organic layers are dried with Na2SO4, filtered and concentrated to give the title compound (0.22 g, 0.55 mmol, 91%). 1H NMR (CDCl3): δ 0.91 (t, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), 1.79-1.95 (m, 4H), 2.41 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 3.32-3.42 (m, 1H), 3.59 (s, 3H), 4.96 (d, J=13.6 Hz, 1H), 5.01 (d, J=13.6 Hz, 1H), 6.73 (s, 1H), 6.76 (t, J=6.7 Hz, 1H), 7.31 (d, J=6.6 Hz, 1H), 7.46 (d, J=6.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C23H29N5O (M+H)+: 392.5. found: 392.3.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([O:21]C)=[O:20])[CH2:15]1.Cl>O1CCOCC1.O.ClCCl>[F:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1/[CH:11]=[CH:12]/[CH2:13][N:14]1[CH2:18][CH2:17][C:16]([CH2:23][CH2:24][CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][C:27]=2[F:38])([C:19]([OH:21])=[O:20])[CH2:15]1
Reactant: COC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(C/C=C/c2cc(F)ccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(C/C=C/c4cc(F)ccc4F)C3)c2c1

Procedure:
1.137 cm3 of a 5 N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.0675 g (0.135 mmol) of the enantiomer B (dextrorotatory) of methyl 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylate in solution in 3 cm3 of dioxane. After stirring under reflux for 48 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 2 cm3 of water and 5 cm3 of dichloromethane. The aqueous phase is acidified with 1 N and then 0.1 N hydrochloric acid to a pH value of 7. The aqueous phase is extracted with twice 5 cm3 of dichloromethane. The organic phases are combined, washed with 5 cm3 of water, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.035 g of the enantiomer B of 1-[(2E)-3-(2,5-difluorophenyl)-2-propenyl]-3-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-3-pyrrolidinecarboxylic acid (absolute configuration not determined) in the form of a beige solid melting at 80–84° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12j and 1-bromo-4-fluorobenzene
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:23](=[O:24])[C@H:21]([CH3:22])[NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=1
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-leucine methyl ester hydrochloride (Sigma) and N-(3,4-dichlorophenyl)-D,L-alanine (from Example A above), the tide compound was prepared as a solid (mp=120-132° C.). The reaction was monitored by tlc (Rf=0.49 in 1:1 EtOAc:Hexanes) and the product was purified by flash chromatography using 1:1 EtOAc:Hexanes as the eluent.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=O.C(O)(=O)C.C([NH2:18])(C)C>>[NH2:18][C@H:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][CH:5]=1)[CH3:1]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)N
Solvent: CC(=O)O
Product: C[C@H](N)c1cccc(O)c1
Temperature: 37 °C

Procedure:
A total of 65 g of the 3-hydroxyacetophenone (compound (1)) substrate was charged to the stirred mixture as a powder. After addition of substrate was complete, the volume of the reaction was topped up to 1 L (if necessary) with the appropriate amount of 0.1 M TBA buffer, pH 7.5. The resulting slurry was stirred at 150 rpm at 37° C. (internal temperature). The temperature was monitored using an external temperature probe. The reaction was conducted under a constant nitrogen sweep of 5 L/min. Additional 5 M isopropylamine acetate (100 mL) was charged to the stirred mixture after 24 h and again after 48 h.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45](C(Cl)=O)=[C:38]2[N:37]=1.O>C1COCC1.CCOC(C)=O.CCOC(C)=O.CCCCCC>[CH3:35][C:36]1[CH:41]=[C:40]([CH3:42])[N:39]2[N:43]=[CH:44][C:45]([C:4](=[O:3])[CH2:5][C:6]3[N:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]4=[N:8][C:7]=3[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:38]2[N:37]=1
Reactant: Cc1cc(C)n2ncc(C(=O)Cl)c2n1
Reactant: CCOC(=O)Cc1c(-c2ccc(OC)cc2)nc2ccc(C)cn12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc3ccc(C)cn3c2CC(=O)c2cnn3c(C)cc(C)nc23)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
To a magnetically stirred solution of [2-(4-methoxy-phenyl)-6-methyl-imidazo[1,2-a]pyridin-3-yl]-acetic acid ethyl ester 13c (0.075 g, 0.231 mmol) in THF (3.0 mL) at −78° C. under Ar atmosphere was added potassium bis(trimethylsilyl)amide (KHMDS) (0.508 mL, 0.5M, 0.254 mmol). The reaction mixture was stirred for 15 min at −78° C., then a THF solution of 5,7-dimethyl-pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (0.053 g, 0.254 mmol) was added. After an additional 60 min at −78° C., water (20 mL) was added, and the reaction mixture was warmed to room temperature. Water was added, and the aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water, dried (MgSO4), and concentrated in vacuo to the crude alkylated product. The crude adduct was dissolved in acetic acid (HOAc) (1 mL) and 12 N HCl (1 mL). The reaction mixture refluxed for 2 h. The mixture was cooled to room temperature and treated with aq Na2CO3 solution until basic. The aqueous solution was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (20 mL), dried (MgSO4), and concentrated in vacuo to the crude product. The pure product was obtained by column chromatography over silica gel, (40:60 EtOAc/hexane, then 100% EtOAc as eluent), which gave the title compound (0.02 g, 20%) as an off white solid. 1H NMR (400 MHz, CDCl3) 2.28 (s, 3H), 2.62 (s, 3H), 2.82 (s, 3H), 3.81 (s, 3H), 4.98 (s, 2H), 6.80 (s, 1H), 6.91 (d, J=8.4 Hz, 2H), 7.02 (d, J=9.1 Hz, 1H), 7.54 (d, J=9.1 Hz, 1H), 7.68 (d, J=9.0 Hz, 2H), 7.76 (s, 1H), 8.62 (s, 1H). Mass spectrum m/e 426 (M+).