Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-]>CO.[Ni]>[I:16][C:13]1[CH:12]=[CH:11][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[CH:6]=[N:7]2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1cnn(-c2ccc(I)cc2)c1
Agent: [Ni]
Solvent: CO
Product: NCc1cnn(-c2ccc(I)cc2)c1
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of 4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (530 mg, 1.63 mmol) and Ra—Ni (50% aq. slurry, 200 mg) in MeOH (3 mL) was hydrogenated under balloon H2 for 1 hr. It was filtered through celite. The filtrate was concentrated in vacuo to give (1-(4-iodophenyl)-1H-pyrazol-4-yl)methanamine (396 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2].[C-:22]#[N:23].[Na+].C(OCC)C.O>CN(C)C=O>[CH2:1]([N:3]([CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:22]#[N:23])[CH:17]=[CH:18][CH:19]=1)[CH2:4]/[CH:5]=[CH:6]/[C:7]#[C:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:2]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
240 mg of (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-bromomethylbenzylamine was dissolved in 4 ml of dimethylformamide, and 61 mg of sodium cyanide was added. The mixture was stirred overnight at room temperature, and then ethyl ether and water were added. The organic layer separated was worked up in a customary manner to give 195 mg of (E)-3-(N-ethyl-6,6-dimethyl-2-hepten-4-ynylaminomethyl)phenylacetonitrile as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7](=O)[C:6]=2[CH:14]=1.[NH2:15][CH2:16]C(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[CH2:16][NH:15][C:7](=[O:8])[C:6]=2[CH:14]=1
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Temperature: 0 °C

Procedure:
As illustrated in the scheme above, a mixture of 6-chloro-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione (6.00 g, 28.4 mmol) and glycine (2.14 g, 28.4 mmol) in glacial acetic acid (72 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo. Water was added to the residue, and the mixture was cooled to 0° C. NaHCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2Cl2 (3×). The combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et2O to provide the title compound as a slightly yellow solid (5.657 g, 89%). 1H-NMR (CDCl3): δ 7.88 (d, J=2.5 Hz, 1H), 7.57 (br s, 1H), 7.53 (dd, J=2.6 Hz, J=8.7 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 3.84 (d, J=6.1 Hz, 2H), 3.39 (s, 3H). MS (ESI) (M+H)+=225.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([O:21]CC)=[O:20])=[C:11]2C)[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]([OH:21])=[O:20])=[CH:11]2)[CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)n(C(C)c2ccc(Cl)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(c1ccc(Cl)cc1)n1cc(C(=O)O)c2ccccc21
Yield: 109.4 %

Procedure:
To a mixture of ethyl 1-(1-(4-chlorophenyl)ethyl)-2-methyl-1H-indole-3-carboxylate (210 mg, 0.61 mmol) in MeOH/H2O (6 mL/2 mL) was added KOH (340 mg, 6.1 mmol) at room temperature. The reaction was refluxed overnight. Then the mixture was adjusted to Ph=4 with 1 N HCl and extracted with EtOAc (3×). The combined organic extract were combined and concentrated in vacuo to afford the title compound as a yellow solid (200 mg, yield 105%) which was used without further purification.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:24]([NH2:27])[CH2:25][NH2:26].C(N(C(C)C)CC)(C)C.[C:37](N1C=CN=C1)(N1C=CN=C1)=[O:38].C(O)(C(F)(F)F)=O>CN1C(=O)N(C)CCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:26]3[CH2:25][CH2:24][NH:27][C:37]3=[O:38])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: NCCN
Solvent: CN1CCCN(C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)c1nc(N2CCNC2=O)c2cccnc2c1O
Temperature: 25 °C

Procedure:
A solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.21 g, 0.55 mmol), ethylene diamine (0.14 mL, 1.67 mmol) and diisopropylethylamine (0.29 mL, 1.67 mmol) in DMPU (2.0 mL) were heated at 140 C for 16 hr. Ethylene diamine (0.14 mL, 1.67 mmol) was added and the reaction heated at 140 C for a further 24 hr. The reaction was cooled to room temperature, and treated with carbonyldiimidazole (0.188 g 1.16 mmol) and diisopropylethylamine (0.29 mL, 1.67 mmol) and then heated at 120 C for 1 hr. The reaction was cooled to room temperature, acidified by the addition of TFA (0.5 mL) and purified by reverse phase HPLC. (Waters PrePak 500 cartridge C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 75 mL/min over 45 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: C1COCCN1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(N3CCOCC3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and morpholine according to general procedure 1 providing the amino compound (235 mg, 85%) as a yellow solid: Rf=0.79 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=9.9 Hz, 1H), 7.53 (s, 1H), 6.81 (d, J=9.9 Hz, 1H), 3.86 (t, J=5.0 Hz, 4H), 3.55 (t, J=4.8 Hz, 4H); ES-MS: (M+H)=283, 285 m/z.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:7]2=1.Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:7]2=1
Reactant: COC(=O)c1cc2c3cc(Cl)ccc3n(C)c2s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cn1c2ccc(Cl)cc2c2cc(C(=O)O)sc21
Yield: 92.6 %

Procedure:
KOH (0.57 g) was dissolved in methanol-water (1/1) (10 ml). (49) (0.50 g) was added and the mixture refluxed for 1 3/4 h. After cooling the mixture was acidified with 1M HCl to pH=1. The precipitate was filtered off, washed with water and dried to give 0.44 g (93%) of (54). M.p. 259°-262° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-])=O)=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4]>O1CCCC1CO.[Ni]>[CH3:1][O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([CH3:39])[CH:31]=3)[C:7]=2[CH2:6]1)=[O:4]
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Ni]
Solvent: OCC1CCCO1
Product: COC(=O)C1Cc2c(ncn2Cc2ccc(N)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Reaction time: 26 h

Procedure:
A solution of 31.2 g methyl-1-(4-nitro-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in tetrahydrofuran-methanol (2:1, 600 mL) is treated with 8.0 g Raney Nickel and placed under an atmosphere of hydrogen at 50 psi for 26 hr. The catalyst is removed by filtration and filtrate is evaporated to give a crisp foam. NMR (CDCl3) 6.77 (s+d,2H,2,6-Ar); 6.60 (d,1H,5-Ar). mp 182°-188° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=C)=[C:6]([NH:10][CH3:11])[N:5]=[CH:4][C:3]=1[C:12]([NH:14][NH:15][C:16](=O)[C:17]([O:19][CH3:20])=[O:18])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:23].O.[OH-].[Na+]>O1CCCC1.O1CCOCC1>[CH3:20][O:19][C:17]([C:16]1[S:23][C:12]([C:3]2[C:2]([Cl:1])=[C:7]3[CH:8]=[CH:11][NH:10][C:6]3=[N:5][CH:4]=2)=[N:14][N:15]=1)=[O:18]
Reactant: C=Cc1c(NC)ncc(C(=O)NNC(=O)C(=O)OC)c1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nnc(-c2cnc3[nH]ccc3c2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
To a suspension of methyl (2-{[4-chloro-6-(methylamino)-5-vinylpyridine-3-yl]carbonyl}hydrazino)(oxo)acetate (450 mg) in tetrahydrofuran (7 ml) and dioxane (7 ml) was added diphosphorus pentasulfide (383 mg) under cooling in an ice bath. After the mixture was stirred at ambient temperature for 5 hours. To the reaction mixture was added tetrahydrofuran (10 ml) and diphosphorus pentasulfide (190 mg). After the mixture was stirred at ambient temperature for 2 hours, water was added to the reaction solution, and the pH was adjusted to approximately 10 with aqueous sodium hydroxide, and the solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol) to obtain methyl-5-(4-chloro-1H-pyrrolo[2,3,b]pyridine-5-yl)-1,3,4-thiadiazole-2-carboxylate (90 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[C:21](=N)(OCC)[CH2:22][CH3:23].CCN(CC)CC>CCO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]2[O:15][C:21]([CH2:22][CH3:23])=[N:17][N:16]=2)=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=N)CC
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1nnc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzohydrazide (6.0 g, 21.4 mmol; reported in Tanaka, A. et al. J. Med. Chem. 1998, 41, 2390) and ethyl propionimidate hydrochloride (3.5 g, 25.7 mmol; preparation reported in WO2007/73299 A1) in EtOH (120 mL) was added Et3N (2.59 g, 25.7 mmol). The mixture was stirred at room temperature for 1 hr then concentrated in vacuo. The residue was partitioned into EtOAc and H2O and the organics were washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (EtOAc-hexanes) gave 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole as a brown oil (3.0 g, 44% yield).
Reaction SMILES: C(OC(N1CC2C(COC3C=C4C(C(OC5C=CC=CC=5N[C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)=[S:41])=NC(F)=N4)=CC=3OC)CCC2C1)=O)C1C=CC=CC=1.C1(CC(Cl)=O)C=CC=CC=1.[CH2:64]([O:71][C:72]([N:74]1[CH2:78][CH:77]2[CH2:79][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH2:101])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:81][CH:76]2[CH2:75]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CCO>C1(C)C=CC=CC=1.CCOC(C)=O.C([S-])#N.[Ag+]>[CH2:64]([O:71][C:72]([N:74]1[CH2:75][CH:76]2[CH2:81][CH:80]([CH2:82][O:83][C:84]3[CH:93]=[C:92]4[C:87]([C:88]([O:94][C:95]5[CH:100]=[CH:99][C:98]([NH:101][C:40]([NH:42][C:43](=[O:51])[CH2:44][C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)=[S:41])=[CH:97][C:96]=5[F:102])=[N:89][CH:90]=[N:91]4)=[CH:86][C:85]=3[O:103][CH3:104])[CH2:79][CH:77]2[CH2:78]1)=[O:73])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: COc1cc2c(Oc3ccccc3NC(=S)NC(=O)Cc3ccccc3)nc(F)nc2cc1OCC1CCC2CN(C(=O)OCc3ccccc3)CC12
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Agent: [Ag+]
Agent: N#C[S-]
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ncnc2cc1OCC1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Yield: 49 %

Procedure:
5-{4-[2-Fluoro-4-(3-phenylacetyl-thioureido-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester. Phenylacetyl chloride (2.65 ml, 20.00 mmol) and AgSCN (4.92 g, 29.6 mmol) were combined in dry toluene (50 ml) and heated to reflux for 2 hrs. The reaction mixture was allowed to cool to room temperature, the solids were filtered through celite and the filtrate concentrated in vacuo. The resulting oil was combined with 5-[4-(4-amino-2-fluoro-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (5.6 g, 10 mmol) in 1:1 EtOH:toluene (100 ml) and the mixture stirred at room temperature for 1-2 hrs. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (3:1 EtOAc:hexanes) to give 5-{4-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-6-methoxy-quinazolin-7-yloxymethyl}-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid benzyl ester (3.61 g, 49%) as a dark brown foam. 1H-NMR (400 MHz, DMSO): 12.44 (s, 1H), 11.80 (s, 1H), 8.54 (s, 1H), 7.90 (m, 1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.38 (s, 1H), 7.34 (m, 7H), 7.28 (m, 3H), 5.05 (s, 2H), 4.16 (d, 2H), 3.94 (s, 3H), 3.72 (s, 2H), 3.48 (m, 2H), 3.30 (m, 2H), 2.65 (m, 2H), 2.52 (m, 1H), 2.10 (m, 2H), 1.30 (m, 2H). LC/MS Calcd for [M+H]+ 736.2, found 736.0.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[Br-:8].[CH2:9]([N+:5]1[CH:6]=[CH:7][N:3]([CH:1]=[CH2:2])[CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: C=Cn1ccnc1
Solvent: CCOC(C)=O
Product: C=Cn1cc[n+](CCCCCCCCCCCCCCCC)c1
Product: [Br-]

Procedure:
15 g of N-vinylimidazole and 50 g of 1-bromohexadecane were stirred in a 500 ml vessel at 60° C. for 8 h. Then, 100 ml of ethyl acetate were added to this mixture while stirring. After a clear solution had formed, the heating and stirring was switched off. A colorless crystalline precipitate formed during the cooling to room temperature and was filtered off and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([NH2:24])[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1>O.CN(C=O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[NH:24][C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2N)C1

Procedure:
(R)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid (17.45 mmol, 4.0 g) and benzene-1,2-diamine (17.45 mmol, 1.87 g) were added to a 100 mL round-bottomed flask equipped for stirring under nitrogen. DMF (30 mL) and 4-methylmorpholine (52.35 mmol, 5.76 mL) were added and the resultant solution was allowed to stir for 5 min at room temperature. N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (20.94 mmol, 4.01 g) and 1H-benzo[d][1,2,3]triazol-1-ol (20.94 mmol, 2.83 g) were then added and the reaction was allowed to stir at room temperature for 16 hr. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed three times with water, two times with saturated aqueous sodium bicarbonate, and once with saturated aqueous sodium chloride. The organic layer was collected and dried with Na2SO4. This mixture was then filtered, the filtrate was collected and concentrated and dried in-vacuo affording (R)-tert-Butyl 3-(2-aminophenylcarbamoyl)piperidine-1-carboxylate (7A) as a brownish foam that was carried directly on to the next step without further purification. ESI-MS: m/z 320.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:11]=[CH:10]2)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Reactant: NCc1ccccc1
Product: Cc1ccc(CNc2ccc3cc(NCc4ccccc4)ccc3n2)o1

Procedure:
The title compound, MS: m/e=344.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and benzylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:17]1([NH:20][CH3:21])[CH2:19][CH2:18]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[N:20]([CH:17]1[CH2:19][CH2:18]1)[CH3:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (R)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (788 mg, 1 eq.), cyclopropyl-methyl-amine hydrochloride (478 mg, 1.2 eq.), HOBt (7.48 mg, 1.5 eq.), EDAC (1.05 g, 1.5 eq.) and TEA (1.5 mL, 3 eq.) in DMF (15 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate and extracted with DCM. The combined DCM was washed with brine, dried, concentrated, purified on a silica gel column to give (R)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]([OH:13])[CH2:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1.O>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:13][CH:10]2[CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:12][CH2:11]2)=[O:31])=[CH:25][CH:24]=1
Reactant: OC1CN=C(c2ccccc2)OC1c1ccccc1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)OC1CN=C(c2ccccc2)OC1c1ccccc1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
A solution of (5RS, 6SR)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.52 g) in anhydrous tetrahydrofuran (10 cc) is added at a temperature in the region of 20° C. to an oily suspension (50% by weight; 0.31 g), maintained under an argon atmosphere, of sodium hydride in anhydrous tetrahydrofuran (20 cc). The mixture is stirred for 30 minutes at the same temperature. A solution of 4-chlorophenyl isocyanate (1 g) in anhydrous tetrahydrofuran (10 cc) is then added dropwise and stirring is continued for 3 hours at a temperature in the region of 20° C. Distilled water (25 cc) is then added and the mixture is extracted with dichloromethane (3×50 cc). The organic phases are combined, washed with distilled water (3×20 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by chromatography on silica (0.063-0.2 mm; 50 g) contained in a column 2 cm in diameter [eluent: ethyl acetate/cyclohexane (2:3 by volume)], collecting 20-cc fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (5RS, 6SR)-5-(4-chlorophenylcarbamoyloxy)-2,6-diphenyl-5,6-dihydro-4H-1,3-oxazine (1 g), m.p. 124° C. is obtained.
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)([CH3:6])[C:3]([OH:5])=O.[NH2:35][CH2:36][CH2:37][OH:38].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CO>[OH:1][C:2]([C:7]1[CH:8]=[C:9]2[C:32](=[CH:33][CH:34]=1)[C:13]1=[N:14][O:15][C:16]([C:17]3[C:21]([C:22]([F:23])([F:25])[F:24])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)=[C:12]1[CH2:11][CH2:10]2)([CH3:6])[C:3]([NH:35][CH2:36][CH2:37][OH:38])=[O:5]
Reactant: CC(O)(C(=O)O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CC(O)(C(=O)NCCO)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To 2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanoic acid (Preparation 134D, isomer 2, 15 mg, 0.032 mmol) in DMF (1 mL) was added 2-aminoethanol (2.9 mg, 0.048 mmol), 4-methylmorpholine (12.9 mg, 0.13 mmol) and BOP (18.3 mg, 0.041 mmol). The reaction mixture was stirred for 1 h. Methanol was added and it was purified by prep HPLC (Phenomenex Luna 5 u 21.2×100 mm, Solvent A: 90% water with 10% acetonitrile and 0.1% TFA, Solvent B: 90% acetonitrile with 10% water and 0.1% TFA, Gradient: 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to yield 2-hydroxy-N-(2-hydroxyethyl)-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)propanamide (5 mg, 9.52 μmol, 29.9% yield) as a white solid: product HPLC ret. time=9.15 min. (condition G); LC/MS M+1=514.06; 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.20 (1H, m), 7.91 (1H, d, J=7.92 Hz), 7.77 (2H, d, J=7.48 Hz), 7.51-7.72 (5H, m), 3.60 (2H, td, J=5.72, 3.08 Hz), 3.36-3.40 (2H, m), 3.07 (4H, s), 1.78 (3H, s).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[O:54][N:53]=[C:52]2[CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:57]=[CH:58][C:51]=12>CN(C=O)C>[N:50]1[O:54][N:53]=[C:52]2[CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:57]=[CH:58][C:51]=12
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3nonc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5nonc5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 85.6 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-benzo[1,2,5]oxadiazol-5-yl-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 88% yield: LCMS (ESI) m/z 414 (MH+).