Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N([OH:49])N=NC=2C=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61]>CN(C=O)C>[NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:61])([CH3:63])[CH3:62])=[O:24])=[CH:26][CH:27]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](=[O:24])([OH:49])[OH:25]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Product: O=C(O)O
Reaction time: 0.5 h
Yield: 115.6 %

Procedure:
To a solution of 4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoic acid (110 mg, 0.29 mmol) in DMF (2 mL) at room temperature was added EDCI (67 mg, 0.35 mmol) and HOBT (48 mg, 0.36 mmol). The solution was stirred for 30 min and tert-butyl (2-aminophenyl)carbamate (85 mg, 0.41 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 20 h and purified by reverse phase HPLC (30% to 95% MeCN in water) to give carbonate tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (105 mg, 64%) as a white solid: 1H NMR (600 MHz, DMSO-d6) δ 10.27 (s br, 2H), 9.83 (s br, 1H), 8.64 (s br, 1H), 7.94 (d, J=8.2 Hz, 2H), 7.60-7.58 (m, 6H), 7.53 (t, J=8.8 Hz, 2H), 7.31 (t, J=8.1 Hz, 41-1), 7.19 (td, J=7.6, 1.5 Hz, 1H), 7.13 (td, J=7.6, 1.5 Hz, 1H), 7.06 (t, J=7.3 Hz, 2H), 4.98 (s, 1H), 1.42 (s, 9H); ESIMS calcd 587.2 (M++Na), found 587.2 (M++Na).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:29][CH3:30])[C:11]=2[CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[CH:6]=1)=[O:4].[OH-].[K+].CO.Cl>C1COCC1.O>[CH3:30][O:29][C:10]1[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2c(CNCc3ccc(OC(F)(F)F)cc3)c(OC)ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2cc(C(=O)O)ccc2c1CNCc1ccc(OC(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a stirred solution of 6-methoxy-5-({[4-(trifluoromethoxy)-benzyl]amino}methyl)-2-naphthoic acid methyl ester (0.286 g, 0.682 mmol) in THF (1.00 mL) at rt was added 1 N KOH (0.682 mL, 0.682 mmol) dropwise. Enough MeOH (˜0.500 mL) was added to make reaction homogeneous. After 1 h at this temperature, the reaction was heated to 45° C. for 2 h. The solution was diluted with H2O (˜2-3 mL) and then acidified to pH 1 with 2 N HCl. The resulting solid was filtered off, washed with H2O and hexane, and dried on the high vacuum for 18 h to afford the product (0.207 g, 69%) as a white solid, mp 235-237° C.; 1H NMR (DMSO-d6) δ3.94 (s, 3H), 4.33 (s, 2H), 4.52 (s, 2H), 7.47 (d, J=8.3 Hz, 2H), 7.59 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.99 (d, J=9.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.60 (s, 1H), 9.14-9.37 (bs, 2H), 12.71-13.25 (bs, 1H); IR (neat) 2520-3100, 1715, 1685, 1630, 1600, 1575, 1510, 1485, 1455, 1295, 1270, 1265, 1210, 1200, 1165, 1110, and 1100 cm−1; mass spectrum [(+) ESI], m/z406 (M +H)+ and [(−) ESI], m/z 404 (M−H)−; Anal. Calcd. for C21H18F3NO4.HCl.0.1H2O: C, 56.86; H, 4.36; N, 3.16, Found: C, 56.45; H, 4.18; N, 3.09.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O-:5])=[O:4].[C:8]([O-])(=O)C.[Na+].[CH3:13][C:14]([CH3:16])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH:14]([NH:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH3:8])=[O:4])([CH3:16])[CH3:13]
Reactant: CC(C)=O
Reactant: CC[C@H](N)C(=O)[O-]
Reactant: CC(=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC[C@H](NC(C)C)C(=O)OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 159.4 %

Procedure:
(2S)-2-Aminobutanoate 41b (13.14 g, 85.52 mmol) was dissolved in 200 mL of dichloromethane. The reaction solution was cooled down to 0° C. in an ice-water bath followed by the addition of sodium acetate (3.51 g, 42.76 mmol), acetone (5.96 g, 0.10 mol) and sodium triacetoxyborohydride (21.75 g, 0.10 mol) successively. The reaction solution was heated to room temperature and stirred for 4 hours. The resulting solution was added with 100 mL of water, added dropwise with saturated sodium carbonate solution to adjust pH to 11 to 12 and separated. The aqueous phase was extracted with dichloromethane (150 mL×2). The combined organic phase was washed with saturated brine (100 mL×2), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain methyl (2S)-2-(isopropylamino)butanoate 43a (10.85 g, yield: 79.7%) as a light yellow oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:10]=[C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:39][CH3:40])=[CH:36][N:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:24][CH:23]=3)=[N:13][N:12]=2)[S:8][CH:7]=1)(=O)C.C1COCC1.CO.[OH-].[Li+]>O>[CH3:40][O:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([O:28][C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:14]4[C:15]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[C:11]([C:9]5[S:8][CH:7]=[C:6]([CH2:5][OH:4])[CH:10]=5)=[N:12][N:13]=4)=[CH:23][CH:24]=3)=[CH:30][CH:31]=[N:32]2)=[N:37][CH:36]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(COC(C)=O)cs5)c5ccccc45)cc3)ccnc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5cc(CO)cs5)c5ccccc45)cc3)ccnc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A scintillation vial was charged with (5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methyl acetate (137 mg, 249 μmol), 1.0 mL 3:1:1 THF:MeOH:water and lithium hydroxide (47.8 mg, 1994 μmol). The homogeneous mixture was stirred at RT for 2 h. Water was added to the mixture, and the precipitated solids were filtered, washed with water, and dried. The crude solids were purified by reverse phase chromatography, Gilson, 10-90% 0.1% TFA/ACN in water to provide (5-(4-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenylamino)phthalazin-1-yl)thiophen-3-yl)methanol. MS: [M+H]=508.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH:12]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:9][C:6]2=[N:7][CH:8]=1.[C-:29]#[N:30].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:14]1([CH2:13][CH:12]([C:10]2[NH:9][C:6]3=[N:7][CH:8]=[C:3]([CH2:2][C:29]#[N:30])[CH:4]=[C:5]3[CH:11]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CCl)cnc3[nH]2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC#N)cnc3[nH]2)cc1
Yield: 17.9 %

Procedure:
A mixture of 5-chloromethyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (798 mg, 1.92 mmol) and sodium cyanide (500 mg, 10.87 mmol) in N,N-dimethylformamide (3 mL) was subjected to microwave irradiation for 0.5 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 5% methanol/dichloromethane) afforded {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetonitrile (140 mg, 18%) as a light yellow solid: LC/MS m/e calcd for C23H25N3O2S [M+H]+ 408.54, observed 408.0; 1H NMR (400 MHz, CDCl3) δ ppm 1.21 (m, 2H), 1.48 (m, 2H), 1.57-1.90 (m, 5H, H), 2.18 (m, 1H), 2.26 (m, 1H), 3.06 (s, 3H), 3.99 (s, 2H), 4.43 (m, 1H), 6.59 (s, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 8.24 (s, 1H), 8.32 (s, 1H), 12.48 (br, 1H).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[C:21]2[C:20]([OH:22])=[C:19]3[C:14]([CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:13][C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1>O.C(#N)C>[F:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[CH:15][C:14]=3[C:13](=[O:2])[C:12]=2[C:11]([O:23][CH3:24])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc(F)c2c(O)c3cnccc3cc12
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COc1ccc(F)c2c1C(=O)c1ccncc1C2=O
Temperature: 60 °C
Yield: 37.2 %

Procedure:
A solution of cerium ammonium nitrate (CAN; 13.70 g) in water (50 mL) is added during twenty minutes to a stirred Suspension of 9-fluoro-10-hydroxy-6-methoxybenzo[g]isoquinoline (1.22 g) in acetonitrile (150 mL). At the end of the addition the obtained suspension is heated at 60° C. for two hours to give a clear, dark solution which is cooled to room temperature and diluted with water (100 mL). Following removal of acetonitrile by distillation at reduced pressure the aqueous phase is saturated with sodium chloride and extracted with methylene chloride (3×150 mL). The combined organic solutions are dried over anhydrous sodium sulphate and the solvent is removed at reduced pressure. The obtained residue is purified by silica-gel column chromatography (eluant: methylene chloride/ethyl acetate from 85/15 to 75/25 v/v) to give 9-fluoro-6-methoxybenzo[g]isoquinoline5,10-dione as a brown-yellow solid (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:34])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)=[C:14]([F:33])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[CH:4][C:3]=1[F:36]>CN(C)C=O.CO.O.NN>[NH2:1][C:2]1[C:7]2[C:8](=[O:34])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[C:14]([F:33])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[CH:4][C:3]=1[F:36]
Reactant: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NCCCNc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h

Procedure:
800 mg of Compound 29 was dissolved in 100 ml of a mixed solvent of dimethylformamide and methanol (1:1), 0.787 ml of hydrazine monohydrate was added and the mixture was stirred at 50° to 60° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol:aqueous ammonia=9:1:1) to give Compound 30 which was dissolved in ethanol, a 5.5N hydrochloric acid-isopropylalcohol solution was added, and the precipitated crystals were collected by filtration to give 321 mg (49%) of hydrochloride of Compound 30.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[C:25](Cl)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:19][C:20]1[C:25]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([F:1])[CH:18]=[CH:17][C:5]=4[N:6]=3)=[CH:15][CH:14]=2)=[N:24][CH:23]=[CH:22][N:21]=1
Reactant: Clc1nccnc1Cl
Reactant: Oc1ccc(Nc2nc3ccc(F)cc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2nc(Nc3ccc(Oc4nccnc4Cl)cc3)sc2c1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol (7.5 g, 0.028 mol) and 2,3-dichloropyrazine (5.0 g, 0.034 mol) in DMSO (35 mL) was added cesium carbonate (11.0 g, 0.034 mol). The mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT and diluted with water (350 mL). The aqueous layer was extracted with EtOAc (4×300 mL). The combined organic extract was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (silica 100-200 mesh; 30-60% ethyl acetate in hexane) to give N-(4-(3-chloropyrazin-2-yloxy)phenyl)-6-fluorobenzo[d]thiazol-2-amine as a white solid. [M+H]=372.8. IC50 (uM) +.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])C.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[Cl:14][C:12]1[S:11][C:9]2[NH:10][C:6]([C:4]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:5])=[CH:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Reactant: C1CNCCN1
Product: O=C(c1cc2cc(Cl)sc2[nH]1)N1CCNCC1
Yield: 35 %

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (102 mg, 0.45 mmol) was hydrolyzed (Procedure B) and then coupled with piperazine (Procedure D) to provide the title compound (42 mg, 35% for two steps) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C11H12ClN3OS, 269.04; m/z found, 270.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): 10.5 (br s,1H), 6.87 (s, 1H), 6.61 (s,1H), 3.87 (t, J=4.8 Hz, 4H), 2.96 (t, J=5.2 Hz, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([OH:16])=[CH:11][CH:12]=2)[CH:7]=1.[Br:21][CH2:22][CH2:23][CH2:24]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:17](=[O:19])[CH3:18])[C:10]([O:16][CH2:24][CH2:23][CH2:22][Br:21])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: COC(=O)COc1ccc2ccc(O)c(C(C)=O)c2c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2ccc(OCCCBr)c(C(C)=O)c2c1
Yield: 95 %

Procedure:
A mixture of 4.989 g of [(8-acetyl-7-hydroxy-2-naphthalenyl)oxy]acetic acid methyl ester, 18 ml of 1,3-dibromopropane and 3.7 g of anhydrous potassium carbonate in 150 ml of anhydrous acetone was stirred at reflux for 16.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on 250 g of silica gel. Elution with 10% ethyl acetate-toluene gave 6.730 g (95% yield) of [[8-acetyl-7-(3-bromopropoxy)-2-naphthalenyl]oxy]acetic acid methyl ester as an oil.
Reaction SMILES: [C:1]1([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[C:14]1([S:20]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:14]1([S:20][C:11]2[S:10][C:9]([C:1]3[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=3)=[CH:13][CH:12]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(-c2cccs2)cc1C
Reactant: ClSc1ccccc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(Sc3ccccc3)s2)cc1C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
A mixture of 37 g (0.197 mole) of 2-(3,4-xylyl)thiophene, 200 ml of reagent carbon tetrachloride, 29 ml (36 g, 0.259 mole) of benzenesulfenyl chloride and 0.05 g of iron powder was allowed to stand two days at room temperature. A vapor phase chromatogram of the mixture showed that all the 2-(3,4-xylyl)thiophene had been consumed. The carbon tetrachloride was removed by distillation and the residue recrystallized from ethanol to give a first crop of 17 g (29%) of 2-phenylthio-5-(3,4-xylyl)thiophene, m.p. 77°-78° C.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH:45][C:46](=[O:58])[C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]=1[C:59]1[CH:67]=[C:66]2[C:62]([CH2:63][N:64]([C@@H:69]([CH:74]([CH3:76])[CH3:75])[C:70]([O:72]C)=[O:71])[C:65]2=[O:68])=[CH:61][CH:60]=1>>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([NH:45][C:46](=[O:58])[C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[CH:49][CH:48]=2)[CH:42]=[CH:41][C:40]=1[C:59]1[CH:67]=[C:66]2[C:62]([CH2:63][N:64]([C@@H:69]([CH:74]([CH3:75])[CH3:76])[C:70]([OH:72])=[O:71])[C:65]2=[O:68])=[CH:61][CH:60]=1
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(OC)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(OC)c2)cc1
Yield: 82.8 %

Procedure:
The compound of example 462 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 461.
Reaction SMILES: [C:1]12([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:14])[O:5]1)[CH2:4][CH2:3][CH2:2]2.C([O-])(=O)C.[K+].[Br:20]Br>C(O)(=O)C>[Br:20][C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:6](=[O:14])[O:5][C:1]3([CH2:4][CH2:3][CH2:2]3)[C:9]=2[CH:10]=1
Reactant: BrBr
Reactant: O=C1Nc2ccccc2C2(CCC2)O1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(Br)cc2C2(CCC2)O1
Yield: 53 %

Procedure:
To a solution of spiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.36 g, 1.9 mmol) and potassium acetate (0.56 g, 5.7 mmol) in acetic acid was added a solution of bromine (0.09 mL, 1.95 mmol) in acetic acid (2 mL) at room temperature. Upon completion by TLC of the reaction, the acetic acid was removed. The residue was treated with saturated sodium bicarbonate (100 mL) and the product extracted with ethyl acetate (50 mL). The organics were dried over magnesium sulfate and concentrated. Trituration of residue with ether gave 6-bromospiro[3,1-benzoxazine-4,1′-cyclobutan]-2(1H)-one (0.27 g, 52%) as a white solid. 1H NMR (DMSO-d6): δ 10.37 (s, 1H), 7.65 (d, 1H, J=2.1 Hz), 7.47 (dd, 1H, J=8.5, 2.2 Hz), 6.86 (d, 1H, J=8.5 Hz), 2.52–2.47 (m, 2H), 2.04–1.98 (m, 2H), 1.87–1.80 (m, 2H). MS (ESI) m/z 268/270 ([M+H]+); MS (ESI) m/z 266/268 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[Cl:13])[N:5]=[CH:4][N:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>CO>[Cl:13][C:9]1[N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH:14]3[CH2:16][CH2:15]3)[CH:7]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Clc1cc(-n2ccnc2Cl)ncn1
Reactant: NC1CC1
Solvent: CO
Product: Clc1nccn1-c1cc(NC2CC2)ncn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
4-Chloro-6-(2-chloro-imidazol-1-yl)-pyrimidine (0.85 g, 4 mmol) and cyclopropylamine (1.4 mL, 20 mmol) were mixed in 10 mL methanol and stirred at 50° C. for 12 hours. After reaction was complete, the solvent was removed by rotary evaporation. The crude product was washed with water and taken to dryness to give the title compound (0.84 g, 90%); 1H NMR 400 MHz (DMSO-d6) δ 8.45 (s, 1H), 8.17 (d, 1H), 7.75 (s, 1 H), 7.08 (s, 1H), 6.80 (d, 1H), 3.34 (s, 1H), 0.78 (br, 2H), 0.52 (br, 2H); MS m/z 236.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[N:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)[O:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([C:22]3[O:21][N:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=4)[N:23]=3)[CH2:25]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1cccc(-c2noc(C3CCCNC3)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccc(F)cc1)N1CCCC(c2nc(-c3cccc(F)c3)no2)C1
Yield: 50 %

Procedure:
The compound was prepared following the procedure described in the Example 3(D), using 4-Fluoro-benzoyl chloride as the acyl chloride of choice and the 3-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine hydrochloride (already prepared before in the Example 9). Yield: 50% (yellow oil); Mp=86-89° C. (beige powder); Rf=0.28 (DCM/MeOH: 98/2); LCMS (Tr): 4.88 min (Method C); MS (ES+) gave m/z: 370.3;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[CH:4][C:3]=1[Cl:11]
Reactant: NCCO
Reactant: Clc1cc(C2CO2)ccc1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCNCC(O)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of (RS)-2-(4-bromo-3-chloro-phenyl)-oxirane (15.2 g) in THF (40 ml) was added 2-aminoethanol (35.1 ml) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was then poured into EtOAc/THF (1:1) and washed with saturated brine. The organic layer was separated and was then dried over Na2SO4 and concentrated in vacuo to afford (RS)-1-(4-bromo-3-chlorophenyl)-2-(2-hydroxyethylamino)ethanol (19.0 g) as a yellow oil which was used in the next step without further purification. MS (ISP): 298.1 ([{81Br37Cl}M+H]+), 296.0 ([{81Br35Cl or 79Br37Cl}M+H]+), 293.9 ([{79Br35Cl}M+H]).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:19]1[C:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=2)=[CH:22][N:21]=[CH:20]1>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[N:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([C:23]3[O:19][CH:20]=[N:21][CH:22]=3)=[N:25][CH:26]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)cn1
Reactant: O=C(O)c1ccc(-c2cnco2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)nc3)C3CC3)CC2)cn1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrazin-2-yl)-piperidin-4-yl]-amine and 6-oxazol-5-yl-nicotinic acid following a procedure analogous to that described in Example 1. LC (method 7): tR=1.05 min; Mass spectrum (ESI+): m/z=419 [M+H]+.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N(CC)CC)C>ClCCl>[CH:1]1([C:5]([NH:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Cyclobutane carbonyl chloride (5 ml, 43.8 mmol) was slowly added to a solution of ethyl glycinate (5.86 g, 42 mmol) in dichloromethane (100 ml) and triethylamine (14.6 ml, 105 mmol) at 0° C. The mixture was then stirred at ambient temperature for 14 hours. The reaction mixture was washed with 1.0 N hydrochloric acid and the organic phase separated, dried (magnesium sulphate) and evaporated in vacuo to yield a yellow solid. Recrystallisation from dichloromethane:petroleum ether, yielded ethyl N-(cyclobutylcarbonyl)glycinate as a white solid (7.78 g, 100% yield):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:10]/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]\[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(C(=C/C=C\C(=O)O)c2cccc(OC)c2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(C(=C/C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cccc(OC)c2)c1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid (1.85 g) and 4-nitrophenol (0.912 g) in dichloromethane (25 mL) was treated with 1,3-dicyclohexylcarbodiimide (1.23 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 2.2 g of crude (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester contaminated with the corresponding (E)-isomer. Purification of the product by HPLC (dichloromethane-hexane; 3:1) yielded 1.2 g of the (Z)-isomer (Z)-5,5-bis(3-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as an oil.