Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.C([O-])(=O)C.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:26][C:25]3[CH:27]=[CH:28][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:23][CH:24]=3)[C:10]=2[N:11]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2ncnc3ccc(Cl)nc23)cc1
Yield: 93.9 %

Procedure:
A mixture of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.200 g, 1.00 mmol), 4-(trifluoromethoxy)aniline (0.177 g, 1.00 mmol) and sodium acetate (0.246 g, 3.00 mmol) in 5 ml of solvent (THF:H2O=1:1) was refluxed for 1 hour. The reaction mixture was diluted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated. The crued was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to get 6-chloro-N-(4-(trifluoromethoxy)phenyl)pyrido[3,2-d]pyrimidin-4-amine (0.32 g, 94%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.30 (1H, d, J=8.4 Hz), 7.72 (1H, d, J=8.8 Hz), 7.98 (1H, d, J=9.2 Hz), 8.15 (1H, dd, J=8.8 Hz), 8.80 (1H, s), 8.90 (1H, br s).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:9])([CH3:8])[CH3:7].CC(C)([O-])C.[K+].IC.CN(P(N(C)C)N(C)C)C>O1CCCC1>[C:6]([O:10][C:11]([N:13]1[C@@H:18]([C@@H:19]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:20]([N:30]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[C:25]([CH3:1])=[C:24]([F:29])[CH:23]=2)[CH2:17][O:16][C@@H:15]([O:53][CH2:54][C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:14]1[CH3:59])=[O:12])([CH3:8])([CH3:7])[CH3:9]
Reactant: [Li]CCCC
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: CN(C)P(N(C)C)N(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)cc(C[C@@H]([C@H](OCc2ccccc2)[C@H]2CO[C@@H](OCC(C)(C)C)[C@H](C)N2C(=O)OC(C)(C)C)N(Cc2ccccc2)Cc2ccccc2)cc1F
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
Add n-butyllithium (252 μL, 0.404 mmol, 1.6 M in hexanes) dropwise over 5 minutes to a solution of (2R,3S,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.30 g, 0.404 mmol) in tetrahydrofuran (0.6 mL) at −78° C. Add potassium tert-butoxide (0.404 mL, 1 M in tetrahydrofuran) dropwise over 10 minutes and stir the reaction mixture for an additional 10 minutes. Add iodomethane (25.1 μL, 0.404 mmol) followed by a solution of hexamethylphosphorus triamide (53.7 μL, 0.294 mmol) in tetrahydrofuran (40.4 μL). Stir reaction mixture at −78° C. for 1 hour. Remove cooling bath and stir for 20 minutes. Add water (20 mL) and extract with ethyl acetate (2×50 mL). Wash combined organic layers with water (3×20 mL), dry over magnesium sulfate, and concentrate under reduced pressure. Subject residue to silica gel chromatography, eluting with hexanes containing 0-10% diethyl ether, to provide the desired compound 0.169 g (55.3%) as a white foam.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added 2-[2-(aminooxy)ethyl]pyridine 125 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373). 1-hydroxybenzotriazole (0.14 g, 1.10 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 91%) as a clear thick oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.CCN=C=NCCCN(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[O:38][C:39]([C:50]([F:53])([F:52])[F:51])=[C:40]([C:42]([NH:44][CH2:45][CH2:46][C:47](O)=[O:48])=[O:43])[N:41]=1.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:47](=[O:48])[CH2:46][CH2:45][NH:44][C:42]([C:40]3[N:41]=[C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[Cl:30])[O:38][C:39]=3[C:50]([F:51])([F:53])[F:52])=[O:43])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(N)cc2)CC1
Reactant: O=C(O)CCNC(=O)c1nc(-c2ccccc2Cl)oc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3nc(-c4ccccc4Cl)oc3C(F)(F)F)cc2)CC1
Reaction time: 24 h

Procedure:
Trans-[4-(4-aminophenyl)cyclohexyl]acetic acid methyl ester (70 mg, 0.28 mmol), EDCI (135.6 mg, 0.71 mmol), 3-{[2-(2-chlorophenyl)-5-trifluoromethyloxazole-4-carbonyl]amino}propionic acid (123.2 mg, 0.34 mmol), HOBt (57.4 mg, 0.23 mmol) and ethyldiisopropylamine (128.3 mg, 0.99 mmol) dissolved in dichloromethane (15 mL) were stirred for 24 hours. The reaction mixture was diluted with aqueous NaHCO3 and extracted with dichloromethane. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to obtain the desired compound (165 mg, 99%) as a white solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[CH2:9]([O:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)=[O:13])[CH3:10].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH:17]2[CH2:18][CH2:19][CH2:20][N:14]([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:15][CH2:16]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1CCNCC1
Reactant: CCOC(=O)N1CCCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCCC(N2CCC(C#N)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 8.9 %

Procedure:
4-cyanopiperidine (0.40 g, 3.62 mmol) was dissolved in MeOH (15 mL), 4-oxoazepane-1-carboxylic acid ethyl ester (0.672 g, 3.62 mmol) and zinc chloride (1.98 g, 14.48 mmol) were added. The reaction mixture was heated for 2 h at 50° C. The solution was then cooled on ice and treated portionwise with sodium cyanoborohydride (0.456 g, 7.24 mmol) and reheated to 50° C. overnight. The reaction mixture was concentrated in vacuo to a white solid. This was dissolved in sat. NH4Cl sol. and extracted with EtOAc (3×50 mL). The combined organics were washed with sat. NaCl sol., dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl 4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate as an oil (0.090 g, 8.9%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C@H:32]([CH3:45])[C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34](O)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C@H:32]([CH3:45])[C@@H:33]([C:34]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CON=C1C[C@@H](c2noc([C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 48 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2S,3R)-3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]butanoic acid, the title compound, 4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl, was obtained in 48% yield (85.9% purity by HPLC).
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.[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][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)([O-:16])=[O:15]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc([N+](=O)[O-])c3)CC2)nc[nH]1

Procedure:
6-[4-(3-Nitro-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 3-nitrobenzaldehyde. Mass spectrum (ES) MH+=316.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH:24]2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][C:44]3[O:49][CH2:48][CH2:47][N:46]([CH2:50][CH2:51][CH2:52][O:53][CH3:54])[C:45]=3[CH:55]=2)=[CH:19][CH:18]=1.[C:56]1(O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:54][O:53][CH2:52][CH2:51][CH2:50][N:46]1[C:45]2[CH:55]=[C:41]([CH2:40][O:39][CH:24]3[CH:23]([C:20]4[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[CH:22][CH:21]=4)[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:30])[CH2:25]3)[CH:42]=[CH:43][C:44]=2[O:49][CH2:48][CH2:47]1
Reactant: Oc1ccccc1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.0819 g of diisopropyl azodicarboxylate is added dropwise to a solution of 0.180 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c), 0.0304 g of phenol and 0.102 g of triphenylphosphine. The solution is stirred at room temperature for 1 hour and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (1:2 EtOAc-heptane); Rt=5.99.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:24][C:25]1[CH:46]=[CH:45][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:33]([F:44])[CH:32]=2)=[CH:27][CH:26]=1.Cl>CN(C)C=O>[F:44][C:33]1[CH:32]=[C:31]([O:30][CH2:29][C:28]2[CH:45]=[CH:46][C:25]([CH2:24][N:10]3[C:11]([CH2:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:12][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9]3)=[CH:26][CH:27]=2)[CH:36]=[CH:35][C:34]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: Fc1ccc(-c2cc(CCc3ccccc3)[nH]n2)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccc(F)cc4)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(4-fluorophenyl)-5-(2-phenylethyl)-1H-pyrazole (300 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 30 min. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 2.56 (2H, t, J=7.6 Hz), 2.78-2.93 (6H, m), 4.12 (2H, q, J=7.2 Hz), 4.98 (2H, s), 5.24 (2H, s), 6.37 (1H, s), 6.59-6.68 (2H, m), 7.03-7.13 (7H, m), 7.19-7.37 (5H, m), 7.77 (2H, dd, J=9.0, 5.5 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](=[O:26])[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([N:1]3[CH:2]=[CH:3][CH:4]=[CH:5]3)[CH:7]=2)=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-n2cccc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-n2cccc2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(1H-pyrrol-1-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-oxo-2-([3-(1H-pyrrol-1-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]([C:13]#[N:14])[C:11]#[N:12])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([CH2:18][CH2:19][F:20])([C:11]#[N:12])[C:13]#[N:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: FCCBr
Reactant: CC(c1ccc(Cl)cc1)C(C#N)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)C(C#N)(C#N)CCF
Yield: 44.6 %

Procedure:
Using 0.41 g of 2-(1-(4-chlorophenyl)ethyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.22 g of 2-(1-(4-chlorophenyl)ethyl)-2-(2-fluoroethyl)malononitrile (the present compound (53)).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)[C:15]2=[NH:31])[CH:5]=1.[OH-].[Na+:34]>CCO>[Na+:34].[Br:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([CH2:13][CH2:12][CH2:11][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([O-:32])=[O:2])[C:15]1=[NH:31]
Reactant: COC(=O)c1cccc(OCCCn2c(=N)n(Cc3cccc(Br)c3)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=c1n(CCCOc2cccc(C(=O)[O-])c2)c2ccccc2n1Cc1cccc(Br)c1
Yield: 85.3 %

Procedure:
To a solution of 3-{3-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid methyl ester (0.50 g, 0.98 mmol) in EtOH (10 ml) at rt is added NaOH (71 mg, 1.77 mmol). The reaction was stirred until the complete consumption of starting material was observed by TLC. After this time, the mixture was concentrated under reduced pressure and then the material that remained was suspended in EtOAc and H2O. The suspension was filtered and the collected solid was dried to provide 3-{3-[3-(3-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid sodium salt (0.42 g, 85%). HPLC-MS 480, 482 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([Br:14])[CH:5]=1.[OH-].[Li+:17]>C1COCC1>[Br:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1)[C:3]([O-:15])=[O:2].[Li+:17]
Reactant: COC(=O)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Br)cc(C(=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 133.1 %

Procedure:
A solution of the commercially available methyl-3-bromo-5-tert-butylbenzoate (87 mg, 0.32 mMol) in THF (2 mL) was treated with 0.5 N aqueous lithium hydroxide (0.71 mL, 0.35 mMol), and the mixture was stirred at room temperature for six hours. The THF was stripped in-vacuo, and the aqueous solution was freeze dried to yield 112 mg of light brown solids. This material was used as-is in the next step.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[CH2:10][C:11]#[N:12]>>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]#[N:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: N#CCBr
Reactant: CCN1CCNCC1
Product: CCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 1-Ethyl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a orange oil; ES-MS: M+=154.1: 1HNMR(DMSO-d6) 3.70 (s, 2H), 2.40-2.20 (m, 10H), 0.95 (t, 3H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:6](=[O:8])[CH:7]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:16][C:17](=[O:18])[C:19]1[CH:24]=[CH:23][C:22]([C:2]2[O:3][C:4]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:5][C:6](=[O:8])[CH:7]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(=O)cc(N3CCOCC3)o2)cc1
Temperature: 90 °C
Yield: 63.3 %

Procedure:
2-Chloro-6-morpholin-4-yl-pyran-4-one (4.01 g, 18.60 mmol), (4-methoxycarbonylphenyl)boronic acid (4.01 g, 22.32 mmol), and ground potassium carbonate (5.64 g, 40.92 mmol) were suspended in dioxane (20 ml) and degassed (sonication for 5 min then saturated with N2). Pd(PPh3)4 (0.5 g, 0.4 mmol) was then added and the reaction mixture was then heated at 90° C. for 24 hrs under a vigorous stirring and a N2 atmosphere. The solvent were removed in vacuo and the residue was then suspended in water 50 ml) and extracted with ethyl acetate (100 ml). The organics were combined, washed with saturated brine and dried over sodium sulphate. The solvent was removed in vacuo and the residue was purified by column chromatography (silica; dichloromethane:methanol; 9:1) to give the title compound as a white solid 3.71 g, 63%). m/z (LC-MS, ESP): 316 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])[CH:6]=[CH:5]2
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Product: O=C(c1ccc2cc(O)ccc2c1)N1CCCC1

Procedure:
The title compound was synthesised from 6-hydroxy-2-naphtoic acid (commercially available) and pyrrolidine (commercially available) according to the procedure described for Example A. MS (m/e): 240.4 (MH−, 100%)
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]([C:30]1[C:34]([CH:35]2[CH2:37][CH2:36]2)=[C:33]([CH:38]2[CH2:41][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:39]2)[O:32][N:31]=1)[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C.O>[CH:35]1([C:34]2[C:30]([CH:21]([CH2:20][CH2:19][OH:18])[CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[N:31][O:32][C:33]=2[CH:38]2[CH2:39][CH:40]([CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:41]2)[CH2:36][CH2:37]1
Reactant: CC(C)CC1CC(c2onc(C(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)CC1CC(c2onc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
tert-Butyl 5-(tert-butyldiphenylsilanyloxy)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]valerate (17.62 g) and tetrahydrofuran (106 mL) were mixed. After an addition of acetic acid/water=4/1 (2.45 mL) and tetrabutylammonium fluoride (1 M in tetrahydrofuran) (39.2 mL) to the solution at ice temperature, the mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/6→1/2) to give the title compound (11.82 g).