Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].C1(C)C=CC=CC=1.[O:16]=[CH:17][C:18](OCC)=O.C(OCC)C>O1CCOCC1>[NH:7]1[C:17](=[O:16])[CH:18]=[N:8][C:2]2[N:1]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C=O
Reactant: Nc1cccnc1N
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=c1cnc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3.8 g of pyridine-2,3-diamine in 100 mL of dioxane, 7.1 g of a 45 to 50% toluene solution of ethyl oxoacetate was added, and the mixture was stirred at room temperature for 1 hour, and then heated under reflux while stirring for 1 hour. The reaction mixture was cooled with ice bath, and diethyl ether was added thereto. The solid was filtered off to obtain 3.9 g of pyrido(2,3-b)pyrazin-2(1H)-one as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:30])([CH2:28][OH:29])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(OCC)(=O)C.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:30])([CH2:28][O:29][S:32]([CH3:31])(=[O:34])=[O:33])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) was dissolved in a mixture of ethyl acetate and tetrahydrofuran (1:2, 30 ml), to which methanesulfonyl chloride (0.18 g) and triethylamine (0.16 g) were added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with water (15 ml×2) and a saturated aqueous solution of sodium chloride (15 ml) successively. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/4) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (330 mg) as a colorless crystalline powder.
Reaction SMILES: [CH2:1]([CH:4]([C:8](=O)[CH3:9])[C:5](=O)[CH3:6])[CH2:2][CH3:3].[C:11]([NH:14][NH2:15])([NH2:13])=[NH:12].[ClH:16]>CO.O.Cl>[ClH:16].[CH3:9][C:8]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([CH3:6])[N:14]([C:11]([NH2:13])=[NH:12])[N:15]=1
Reactant: N=C(N)NN
Reactant: CCCC(C(C)=O)C(C)=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CCCc1c(C)nn(C(=N)N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 2.06 g of 3-propyl-2,4-pentanedione in 10 ml of methanol was added little by little to a solution of 1.56 g of aminoguanidine hydrochloride in 5 ml of water, 30 ml of methanol and 1 ml of concentrated hydrochloric acid, and stirred overnight at room temperature. The solvents were removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ethanol-ether to obtain 1.70 g of 3,5-dimethyl-4-propyl-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC([CH:14]=[O:15])=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([F:41])=[C:32]([N:35]4[CH2:39][CH2:38][CH:37]([N:40]=[CH:1][C:2]5[CH:7]=[CH:6][C:5]([O:15][CH3:14])=[CH:4][CH:3]=5)[CH2:36]4)[CH:33]=3)[C:28](=[O:42])[C:27]([C:43]([OH:45])=[O:44])=[CH:26]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(C=O)cc1
Reactant: O=Cc1ccccc1
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2)C1
Product: COc1ccc(C=NC2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4-c3ccc(F)cc3)C2)cc1

Procedure:
In the described fashion of Example 1 replacing benzaldehyde with 4-aminobenzaldehyde and using the acid (1) (R=cyclopropyl) described in Example 19 one obtains 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-(4-aminobenzylidene)amino-1-pyrrolidinyl)-quinoline-3-carboxylic acid (3) (R=cyclopropyl, Z=p-aminophenyl).
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(OCC)(OCC)[O:12][CH2:13][CH3:14].[CH2:21](O)[CH3:22]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:21]([O:1][C:2]([O:12][CH2:13][CH3:14])([CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:22]
Reactant: CCO
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CCC(C)(OCC)OCC
Yield: 72.5 %

Procedure:
A mixture of 171.3 g (1.19 mol) of ethyl 4-oxopentanoate, 207 ml (184.2 g, 1.24 mol) of triethyl orthoformate, 26 ml of absolute ethanol and 1 g of p-toluenesulfonic acid was refluxed for 8 h with vigorous stirring and then distilled under reduced pressure. 187.9 g (72.5%) of ethyl 4,4-diethoxypentanoate were obtained, boiling point 104-106° C./14 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].NC1C=CN=CC=1Cl.C1COCC1.[N:32]12[CH2:40][CH2:39][CH2:38][C@H:37]1[CH2:36][NH:35][CH2:34][CH2:33]2>C(N(CC)CC)C>[CH2:36]1[N:35]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:34][CH2:33][N:32]2[CH2:40][CH2:39][CH2:38][C@@H:37]12
Reactant: C1C[C@H]2CNCCN2C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Nc1ccncc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCN4CCC[C@H]4C3)s2)noc1C(F)(F)F
Yield: 85 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 4-amino-3-chloropyridine by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and (S)-1,4-diazabicyclo[4.3.0]nonane. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a saturated aqueous NaHCO3 solution followed by water to afford product as a yellow colored solid (82 mg, 85%). 1H NMR (CDCl3) 1.34-1.48 (m, 1 H), 1.70-1.90 (m, 3 H), 1.92-2.20 (m, 1 H), 2.10-2.26 (m, 2 H), 2.32 (d, J=1.3, 3 H), 2.80 (br s, 1 H), 3.03-3.11 (m, 2 H), 3.20 (obs br s, 1 H), 4.40 (br s, 2 H), 7.29 (d, J=4.0, 1 H), 7.41 (d, J=3.5, 1 H). 13C NMR 7.9, 21.3, 27.5, 30.0, ˜48 (br), 51.8, 53.5, 62.8, 114.7, 118.7 (q, J=271), 128.0, 129.3, 131.2, 140.2, 155.2 (q, J=40), 157.9, 162.9. 19F NMR −63.1. LC/MS 4.34 min, [M+1]+ 386.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>CO.O>[CH:1]1([CH2:4][CH:5]([C:22]2[CH:36]=[CH:35][C:25]([C:26]([NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:23]=2)[O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[N:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)c1ccc(C(CC2CC2)Oc2ccc(-n3cc(C(F)(F)F)cn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of methyl 3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 0.18 mmol) in methanol (0.9 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to pH=6. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/−)-3-(4-(2-cyclopropyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)ethyl)benzamido)propanoic acid (52 mg, 59%). 1HNMR (400 MHz, CD3OD, δ): 8.47 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 6.92 (d, 2H), 5.34 (m, 1H), 3.53 (m, 2H), 2.48 (m, 2H), 1.98-1.94 (m, 1H), 1.60-1.58 (m, 1H), 0.75-0.77 (m, 1H), 0.42-0.33 (m, 2H), 0.08-0.01 (m, 2H). MS (M+Na): 510.3.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([C:9](Cl)=[O:10])[CH2:2]2.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1.ClCCl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=1)=[O:10])[CH2:2]2
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc(NC(=O)[C@@H]3CN4CCC3CC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
679 mg (3.91 mmol) of (3R)-1-azabicyclo[2.2.2]octane-3-carbonyl chloride, 846 mg (3.73 mmol) methyl 4′-amino-1,1′-biphenyl-4-carboxylate, 963 mg (7.45 mmol) of N,N-diisopropylethylamine and 227 mg (1.86 mmol) of 4-N,N-dimethylaminopyridine are dissolved in 5 ml of THF and stirred at RT overnight and then at 50° C. overnight once again. The reaction mixture is taken up in dichloromethane and water, and the aqueous phase is extracted three times with dichloromethane. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane/triethylamine 100:1→dichloromethane/methanol/triethylamine 50:50:1). The solvent is removed under reduced pressure. The product is taken up in 1N sodium hydroxide solution and extracted a total of three times with ethyl acetate. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 50 mg (4% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)[O:3]1.CC[N:22]=C=NCCCN(C)C.Cl.O>CN(C=O)C>[CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OB(c2ccc(CC(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (500 mg) and HOBt ammonium salt (435 mg) in DMF (5 mL) was added EDCI hydrochloride (539 mg), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (420 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[N:26]1([C:32]2[S:33][C:34]([C:37](O)=[O:38])=[CH:35][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:24][N:23]([CH3:25])[C:21]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:37]([C:34]1[S:33][C:32]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[N:36][CH:35]=1)=[O:38])=[CH:10][CH:9]=[C:8]([Cl:14])[CH:7]=2)=[O:22]
Reactant: O=C(O)c1cnc(N2CCOCC2)s1
Reactant: CN(C)C(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Product: CN(C)C(=O)c1c(CNC(=O)c2cnc(N3CCOCC3)s2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
7-Chloro-3-{[(2-morpholin-4-yl-thiazole-5-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide was prepared starting from intermediate C and 2-morpholin-4-yl-thiazole-5-carboxylic acid. MS calcd. for C27H26ClN5O4S [(M+H)+] 552.1, obsd. 552.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:16].C[Mg+].[Br-].[Li]C(C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=1)[CH:29]=[O:30]>C1COCC1.CO>[Cl:25][C:26]1[CH:27]=[C:28]([CH:29]([OH:30])[C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=2[F:16])[CH:31]=[CH:32][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(F)c1
Reactant: O=Cc1ccnc(Cl)c1
Agent: C[Mg+]
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(O)c2ccnc(Cl)c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
To a solution of tert-butyl 4-bromo-3-fluorophenylcarbamate (2.60 g, 9.0 mmol) in anhydrous THF (30 mL) at −78° C. was added MeMgBr (3.0 M in Et2O, 3.1 mL, 9.3 mmol) via syringe. The solution was stirred for 10 min at that temperature, and then warmed to 0° C. for 0.5 h. After the solution was cooled back to −78° C., a solution of t-BuLi (1.7 M in hexane, 10.6 mL, 18.1 mmol) was added over 4 min. The resulting solution was allowed to stir for 5 min before a solution of 2-chloroisonicotinaldehyde (1.41 g, 10 mmol) (for preparation, see Frey, L. F. et al. Tetrahedron Lett. 2001, 42, 6815) in anhydrous THF (25 mL) was added in 3 min. The reaction mixture was stirred at −78° C. for 20 min and 2.0 mL of MeOH was added. The solution was then concentrated under reduced pressure and the residue was dissolved in 200 mL of EtOAc. It was subsequently washed with H2O (2×50 mL), brine (2×50 mL) and dried over MgSO4. After filtration and concentration, the residue was purified by flash chromatography on SiO2 eluting with 0%-50% EtOAc in hexane to give tert-butyl 4-((2-chloropyridin-4-yl)(hydroxy)methyl)-3-fluorophenylcarbamate (1.30 g, 41% yield). MS (ESI+): m/z 353.28/355.24 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].[Cl:26][C:27]1[C:28]([CH2:39]Cl)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1.O>CN(C)C=O>[Cl:26][C:27]1[C:28]([CH2:39][O:25][C:22]2[CH:21]=[CH:20][C:19]([CH2:18][N:8]3[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:5][CH2:3][CH3:4])=[N:7]3)=[CH:24][CH:23]=2)=[N:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1nc(-c2ccccc2)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)ccc3Cl)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 3-chloro-2-chloromethyl-6-phenylpyridine (357 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridylmethoxy)benzyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (740 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH:19]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28](Br)[CH:27]=1)(=[O:25])=[O:24])([CH3:21])[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:28]1[CH:27]=[C:26]([S:23]([NH:22][CH:19]([CH3:20])[CH3:21])(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[CH3:32])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)NC(C)C)cc1Br
Product: Cc1ccc(S(=O)(=O)NC(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-isopropyl 3-bromo-4-methylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][CH:2]([F:29])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)[O:17][CH:18]=1.[CH2:30](I)[CH3:31]>>[F:29][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:28])[CH2:12][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:30][CH3:31])[CH:20]=2)[O:17][CH:18]=1
Reactant: CCI
Reactant: COc1ccc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)cc1O
Product: CCOc1cc(-c2nc(CCC(=O)c3ccccc3OCC(F)F)co2)ccc1OC

Procedure:
Using the compound obtained in Example 272 and ethyl iodide, white powdery 1-[2-(2,2-difluoroethoxy)phenyl]-3-[2-(3-ethoxy-4-methoxyphenyl)oxazol-4-yl]propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].O>CN(C)C=O>[CH3:12][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:16][CH2:17][CH2:18][N:19]2[C:23](=[O:24])[C:22]3[C:21](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]2=[O:29])=[CH:7][CH:6]=1
Reactant: CN(C)CCc1ccc(O)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCc1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-[2-(dimethylamino)ethyl]phenol (4.13 g) and sodium hydride (0.67 g) in dimethylformamide was stirred at room temperature for 24 h. N-(3-Bromopropyl) phthalimide (6.7 g) was added at 0° and stirring was continued for 24 h. The solution was treated with water and extracted with ether. Evaporation of the solvent gave the title compound as a white solid which was recrystallised from light petroleum (b.p. 60°-80°) 2.3 g) m.p. 81°-82°. TLC silica; ethyl acetate:water:isopropanol:0.88 ammonia 25:8:15:2; Rf 0.45.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=1)[NH2:17])[CH3:13].C(N(CC)CC)C>O1CCOCC1>[CH2:12]([O:14][C:15](=[O:30])[CH:16]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:20]=1)[NH:17][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C(N)Cc1cccc(NS(C)(=O)=O)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1cccc(NS(C)(=O)=O)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 10°-15° C., add benzylchloroformate (15.5 mL) dropwise to a heterogeneous mixture of 3-methanesulfonamido-D,L-phenylalanine ethyl ester (25.00 g) and triethylamine (15 mL) in dioxane (400 mL). Warm to room temperature, stir overnight, and remove the dioxane in vacuo. Partition the mixture between EtOAc (200 mL)/water (500 mL). Wash the EtOAc solution with water (500 mL), 1N HCl (500 mL), 5% NaHCO3 (500 mL), and brine (500 mL). Concentrate the dried (MgSO4) EtOAc solution in vacuo to a residue. Chromatograph the residue on silica gel (40μ, 2200 mL) using EtOAc:hexane (3:7) as eluant to give N-benzyloxycarbonyl-3-methanesulfonamido-D,L-phenylalanine ethyl ester.
Reaction SMILES: [C:1]1([N-:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][CH2:18][CH2:19][C:20](Cl)=O.B.C1(N(CCCBr)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]1([N:7]([CH2:20][CH2:19][CH2:18][Br:17])[C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCBr
Reactant: O=[N+]([O-])c1ccc([N-]c2ccccc2)cc1
Agent: B
Agent: BrCCCN(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N(CCCBr)c2ccccc2)cc1

Procedure:
3-[N-phenyl-N-(4-nitrophenyl)amino]-1-bromopropane is prepared from N-phenyl-N-(4-nitrophenyl)amide with 3-bromopropionyl chloride, followed by reduction with borane in tetrahydrofuran, by a procedure analogous to the preparation of 3-[N,N-diphenylamino]-1-bromopropane in Example 2.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([O:27]C)=[O:26])[CH:21]=2)[CH:15]=1)=[O:8].C1COCC1.CO.[OH-].[Na+].Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:24][CH:23]=[C:22]([C:25]([OH:27])=[O:26])[CH:21]=2)[CH:15]=1)=[O:8]
Reactant: COC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)O)c[nH]3)c2)c1
Temperature: 68 °C

Procedure:
To a stirred solution of methyl 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylate (1.30 g, 3.12 mmol) in a mixture of solvents THF/MeOH (10 ml/10 ml) was added 2 ml of 5M NaOH (10 mmol) solution. The mixture was heated in a 68° C. bath for 8 hours, cooled to room temperature and poured into 200 ml of water. 2M HCl was added until pH=3. The resulting precipitates were filtered, washed with water, and dried in vacuo to give 5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrole-3-carboxylic acid as white solid. Yield: 1.20 g, 95%.