Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C(O)=O.C([O:11][C:12](=[O:26])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:15]1=[O:25])(C)(C)C.[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50](O)=[O:51])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:27]([O:34][C:35]([NH:37][C@H:38]([C:50]([N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([OH:11])=[O:26])[C:15](=[O:25])[C@@H:16]1[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:51])[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][CH:45]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Reactant: COC(=O)c1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)[C@H](Cc1ccc(C(=O)OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
In 7.6 ml of methylene chloride were dissolved 0.76 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid t butyl ester oxalic acid salt and 0.47 g of N-benzyloxycarbonyl-4-methoxycarbonyl-L-phenylalanine. To the solution was added gradually, while cooling with water, 0.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, over 5 minutes. The mixture was stirred for one hour at room temperature, then methylene chloride was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by means of a silica gel chromatography (hexane/ethyl acetate=l/2) to give 0.46 g (51.1%) of the title compound as a colorless oily product.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([OH:28])([CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1)[CH2:4][C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:7])[CH3:6].ClC(Cl)C.C(O)(=O)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[OH:28][C:3]([C:2]([F:30])([F:1])[F:29])([CH2:4][C:5]([CH3:6])([C:8]1[CH:15]=[CH:14][CH:13]=[C:10]([CH2:11][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:9]=1)[CH3:7])[CH2:16][N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[CH:19]=[CH:18]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C=O)c1
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
To a solution of 3-[4,4,4-trifluoro-3-hydroxy-1,1-dimethyl-3-(4-oxo-4H-quinolin-1-ylmethyl)butyl]benzaldehyde (0.05 g, 0.12 mmol), dichloroethane (3.0 mL), and acetic acid (0.09 mL, 1.46 mmol) in an ice bath was added morpholine (0.26 μL, 3.00 mmol). The solution was warmed to room temperature and stirred for 0.5 hours. Triacetoxy sodium borohyride (0.06 g. 0.30 mmol) was added and the reaction stirred at room temperature. After 3.0 hours, the solution was partitioned between EtOAc and 3% NH4OH (3 mL). The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The product was eluted from a flash chromatography column with EtOAc/hexanes, and concentrated in vacuo to afford 1-[2-hydroxy-4-methyl-4-(3-morpholin-4-ylmethylphenyl)-2-trifluoromethylpentyl]-1H-quinolin-4-one as a colorless solid (0.03 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26]Cl)=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:30]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][I:30])=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCCl)cc1
Reactant: [I-]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCI)cc1

Procedure:
Chloromethyl 4-(N-benzyloxycarbonyl-L-valyloxy)benzoate was converted to iodide by the method described in Example A-I-1, step e to give the title compound (1.16 g) practically pure. Rf (2%MeOH/CHCl3) 0.80.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CCO.O>[C:1]([O:4][CH:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][CH:14]2[OH:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(O)CC[C@@H]32)C1

Procedure:
To a solution of 100 mg. (0.303 mmol) of 3-acetoxy-androst-5-en-17-one, 1, in 3 ml EtOH at -10° C., was added 22.9 mg (0.606 mmol) of sodium borohydride with stirring. After the reaction mixture was stirred for one and 1/2 hours, the mixture was diluted with 10 ml water, the ethanol solvent removed under vaccum, and the residue extracted with ethyl acetate. The organic layer was washed with aqueous Na2CO3, brine, dried over sodium sulfate and concentrated to leave a residue of crude title compound 2. Proton NMR confirmed the assigned structure.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:17](=[O:18])[CH2:16][N:15]=[C:14]([N:19]3[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[N:21]=[CH:20]3)[CH:13]=[C:7]12.CO[C:29]1C=CC=C(OC)[C:34]=1[C:35]1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CO>[CH:35]1([C:2]2[C:11]([F:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][N:6]2[C:17](=[O:18])[CH2:16][N:15]=[C:14]([N:19]4[CH:23]=[C:22]([CH2:24][O:25][CH3:26])[N:21]=[CH:20]4)[CH:13]=[C:7]23)[CH2:34][CH2:29]1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(ccc(F)c4Br)C3=C2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: COCc1cn(C2=NCC(=O)N3CCc4c(ccc(F)c4C4CC4)C3=C2)cn1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
Example 96-2. 9-bromo-10-fluoro-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (1.5 g, 3.58 mmol) was dissolved in toluene (36 mL) and S-Phos (0.47 g, 1.14 mmol), cyclopropylboronic acid (0.615 g, 7.16 mmol) and K3PO4 (1.59 g, 7.51 mmol) were added. The suspension was degassed, Pd(OAc)2 (0.16 g, 0.72 mmol) was added under Argon and the mixture was heated at 100° C. for 1.5 h. The mixture was allowed to warm to RT and filtered through a pad of celite. The residue was diluted with DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 50% AcOEt in DCM for 5 min, then from 50% AcOEt in DCM to 100% AcOEt in DCM in 40 min, followed by 100% AcOEt in DCM for 10 min)) to yield a foam. A second flash-column chromatography over silicagel was done (Biotage Isolera Four, eluent: 0.5% MeOH in DCM for 4 min, then from 0.5% MeOH in DCM to 4% MeOH in DCM in 60 min, 4% MeOH in DCM for 20) to yield the title compound as a yellow solid. The residue was dissolved in DCM and MP-TMT resin (0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol to afford the title compound as white crystals (683 mg). UPLC-MS: MS 381.3 (M+H+); UPLC rt 3.53 min (10 min method). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.55-0.64 (m, 2 H), 0.94-1.04 (m, 2 H), 1.67-1.78 (m, 1 H), 3.08 (t, J=5.99 Hz, 2 H), 3.23 (s, 3 H), 3.77-3.88 (m, 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 7.10-7.20 (m, 2 H), 7.63 (s, 1 H), 7.98 (dd, J=8.93, 5.01 Hz, 1 H), 8.20 (d, J=1.47 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH2:9].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11]>>[F:8][C:4]1[C:3]2[NH:9][C:10](=[O:11])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc(F)c1N
Product: O=c1[nH]c2cccc(F)c2[nH]1

Procedure:
The title compound was prepared by the method of Preparation 24 from 1,2-diamino-3-fluorobenzene [J.O.C. 1969, 34(2), 384] and 1,1′-carbonyldimidazole.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[NH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][NH:25][C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:5]=1)=[O:3])#[N:33]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: N#Cc1cccc(OCCN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C(=O)NCCOc3cccc(C#N)c3)cc2)CC1

Procedure:
1.60 g (4.8 mmol) of t-butyl 4-(4-carboxybenzoyl)piperazine-1-carboxylate, 1.58 g (8.0 mmol) of 3-(2-aminoethoxy)benzonitrile, 1.67 ml (12 mmol) of triethylamine, 650 mg (4.8 mmol) of 1-hydroxybenzotriazole and 920 mg (4.8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were stirred in 20 ml of dimethylformamide at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][CH2:45][CH:46]=O)[CH2:39]1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([CH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([CH2:44][CH2:45][CH:46]=[CH:2][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:39]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)C1CCCC(CCC=O)C1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)(C)C1CCCC(CCC=CCc2ccccc2)C1
Yield: 61.1 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (2.60 g, 5.81 mmol, 1.0 equiv.), n-BuLi (1.3 M in hexanes, 4.5 mL, 5.81 mmol, 1.0 equiv.) and 3-(3-tert-butylcyclohexyl)propanal (1.45 g, 7.39 mmol, 1.3 equiv.), 1.01 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=2)=[O:11])=[N:27][CH:28]=1
Reactant: Fc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccnn2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(F)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-5-yl)phenyl)methanone and 2-bromo-5-fluoropyridine. ESI-MS (m/z): 422 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[CH3:28][S-:29].[Na+]>O1CCOCC1.CN(C=O)C>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([S:29][CH3:28])[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(SC)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium methanethiolate in dioxane and DMF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:27]([F:30])([F:29])[F:28].[OH-].[K+].Cl>O1CCCC1.CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:27]([F:30])([F:28])[F:29])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-trifluoromethyl-benzoic acid methyl ester (Example I13) (4.3 g) in tetrahydrofuran (3 ml) and methanol (3 ml) was added a solution of potassium hydroxide (1.0 g) in water (4.0 ml). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was acidified by addition of hydrochloric acid (2M) (200 ml) and the mixture extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was re-crystallized from dichloromethane and heptane to give 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-trifluoromethyl-benzoic acid (3.58 g) as a white powder. 1H-NMR (CDCl3, 400 MHz): 8.08-7.45 (m, 6H), 4.14 (d, 1H), 3.76 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C([O-])(=O)C.[Na+]>C(O)CC>[Cl:1][C:2]1[N:3]([CH2:13][C:11]([OH:12])([CH3:10])[CH2:14][N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(CC2(C)CO2)CC1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCCO
Product: CC(O)(CN1CCCN(C(=O)OC(C)(C)C)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 26.3 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (8.39 g, 56.88 mmol), tert-butyl 4-(2-methyloxiran-2-ylmethyl)homopiperazine-1-carboxylate (15.38 g, 56.88 mmol) and sodium acetate (5.13 g, 62.57 mmol) in 1-propanol (100 ml) was stirred under reflux for 10 hours. The reaction mixture was allowed to return to room temperature and then concentrated under reduced pressure. The residue was dissolved in methylene chloride. The solution was washed with water, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=5/1) to afford tert-butyl 4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]homopiperazine-1-carboxylate (6.25 g, yield 27%) as a reddish yellow oil.
Reaction SMILES: O.[OH:2][C:3]1[C:11]2[N:10]=NN[C:7]=2[CH:6]=CC=1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([OH:53])=O)=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1.N[C@H](CC)CO>C1COCC1>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]([CH2:45][O:46][C:47]3[CH:55]=[CH:54][C:50]([C:51]([NH:10][C@@H:11]([CH2:3][OH:2])[CH2:7][CH3:6])=[O:53])=[CH:49][N:48]=3)=[C:43]([CH2:56][OH:57])[O:42][N:41]=2)=[CH:36][CH:35]=1
Reactant: Oc1cccc2[nH]nnc12
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CC[C@@H](N)CO
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](CO)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
Hydroxybenzotriazole hydrate (45.3 mg, 0.29 mmol), N-ethyldiisopropylamine (253 μL, 1.45 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (56.7 mg, 0.29 mmol) were added at 0° C. to a solution of 6-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) and (R)-(−)-2-amino-1-butanol (34.0 μL, 0.35 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature overnight. Extraction with 1 N aqueous hydrochloric acid/ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:1 to 100:0) afforded the title compound (60 mg, 50%) as a white solid. MS: m/e=414.2 [M−H]−.
Reaction SMILES: [C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][N:37](C(OCC2C=CC=CC=2)=O)[C:38](=[NH:50])[NH:39]C(OCC2C=CC=CC=2)=O)[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[ClH:62].O1CCOCC1.[H][H]>CN(C=O)C.[Pd]>[ClH:62].[C:1]1([O:11][C:12](=[O:61])[C@H:13]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[NH:39])[NH2:50])[NH:14][C:15](=[O:33])[C@H:16]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: N=C(NC(=O)OCc1ccccc1)N(CCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)Oc1cccc2ccccc12
Yield: 92 %

Procedure:
In 10 ml of DMF was dissolved 1.07 g of the above ester, after which 0.5 g of 10% Pd-C and 1.65 ml of 2 N hydrochloric acid-dioxane solution were added thereto. The mixture was stirred with ice-cooling for 3 hrs while passing hydrogen gas therethrough. After the reaction, the reaction mixture was filtered to remove the Pd-C, and 500 ml of anhydrous diethyl ether was added to the filtrate. The white powder thus precipitated was collected and vacuum-dried over P2O5 at 110° C. for 3 hrs to obtain 700 mg (yield 92%) of benzoyl-L-phenylalanyl-L-arginine 1-naphthyl ester hydrochloride, m.p. 112° C.-(decomp.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1.C(N(C(C)C)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20])(C)C>C(Cl)Cl>[C:19]([O:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([Cl:12])[CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: OCCNc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OCCNc1ccc(F)c(Cl)c1
Yield: 59.9 %

Procedure:
N-2-hydroxyethyl-3-chloro-4-fluoroaniline (1.48 g, 7.81 mmol) in CH2Cl2 (20 ml) was reacted with N,N-diisopropyl O-tert-butyl-isourea (6.25 g, 31.2 mmol) at room temperature over night. The product was purified by silicagel chromatography, Eluant, ether/petroleum ether 5/95, 10/90 to give title compound (1.15 g, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][CH:8]=1.[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1>[C:9]1([S:15]([NH:1][CH2:2][CH2:3][C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCc1ccco1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=S(=O)(NCCc1ccco1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.2 g of 2-(2-aminoethyl)-furan are dissolved in 45 ml of pyridine and at 5° C. a solution of 8.8 g of benzenesulphonic acid chloride in 50 ml of pyridine is added. The resulting mixture is then stirred overnight at ambient temperature, the reaction product is evaporated down, the residue is taken up in water and extracted with methylene chloride. After the organic phase has been dried over magnesium sulphate the solution is concentrated by evaporation and chromatographed over a silica gel column using ethylene chloride.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:14])[CH2:8][CH2:9][C:10]([O:12]C)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[N:14]([CH2:27][C:23]2[CH:22]=[C:21]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=2)[C:10](=[O:12])[CH2:9][CH2:8]1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCC(N)c1ccccc1-c1ccccc1
Product: O=C1CCC(c2ccccc2-c2ccccc2)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-([1,1′-biphenyl]-2-yl)-4-aminobutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=1.01 min.; [M+H]+: 403.91 g/mol.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O>C(#N)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[N:7]=[C:6]2[N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1n[nH]c2nc(F)ccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nn(C(=O)OC(C)(C)C)c2nc(F)ccc12
Reaction time: 1 h

Procedure:
A stirred solution of 6.67 g (44.2 mmol) of 6-fluoro-3-methyl-1H-pyrazolo[3,4-b]pyridine in 100 mL of acetonitrile under nitrogen was treated with 5.40 g (44.2 mmol) of DMAP and 6.46 mL (46.4 mmol) of triethylamine. A solution of 11.56 g (53.0 mmol) of (BOC)2O in 20 mL acetonitrile was added dropwise via a cannula and the resulting reaction mixture stirred for 1 hour until completion as determined by LC/MS analysis. The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic layers were washed with H2O, brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified via silica gel chromatography (0-70% EtOAc/hexane) to yield the title compound. 1H NMR (CDCl3): 1.74 (s, 9H), 2.60 (s, 3H), 6.95 (d, 1H), 8.08 (t, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:30]>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.52 g (10 mmol) of 1-diphenylmethylpiperazine and 1.11 g (11 mmol) of triethylamine were dissolved in 30 ml of isopropanol, followed by addition of a solution obtained by dissolving 2.15 g (10 mmol) of α-bromo-p-hydroxyacetophenone in 20 ml of isopropanol. The mixture was allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration. The crystals were successively washed with isopropanol, water and isopropanol and then dried to give 3.27 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 84.6%).