Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1>CCO>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH:1][C:2]2[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCO
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1[N+](=O)[O-]

Procedure:
Ethyl 2-amino-5-ethyl-thiophene-3-carboxylate and 5-bromo-2-fluoronitrobenzene, m.p. 76°-78° C. (EtOH).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10]=[N:11][NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:14](O)([CH3:17])([CH3:16])[CH3:15].FC(F)(F)C(O)=O.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:10]=[N:11][N:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:13]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Cc2nn[nH]n2)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnc(Cc2ccc(Br)cc2)n1
Yield: 54 %

Procedure:
A mixture of 5-[(4-bromophenyl)methyl]-2H-tetrazole (18.5 g. 77 mmol). t-butanol (11.4 g. 150 mmol), trifluoroacetic acid (76 mL. 1.0 mol) and concentrated sulfuric acid (3.8 g. 39 mmol) was stirred for 24 h and then partitioned between ethyl acetate (250 mL) and water (100 mL). The organic layer was washed with water (4×100 mL) and 1M NAOH (2×100 mL) and was dried over sodium sulfate. Filtration and removal of the solvent in vacuo produced a solid that was recrystallized from hexane to give 5-[(4-bromophenyl)methyl]-2-(1,1-dimethylethyl)-2H-tetrazole. (12.3 g, 47 mmol) in 54% yield, mp. 69°-70° C.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([O:4][C:5]([C@H:7]([NH:25][C@H:26]([C:31]([OH:33])=O)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])=[O:6])[CH3:3].ONC(=O)CCC(N)=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.Cl.[NH:61]1[C:65]([CH2:66][NH2:67])=[N:64][N:63]=[N:62]1>CN(C=O)C.C(N(CC)CC)C>[CH3:3][C:2]([O:4][C:5](=[O:6])[C@H:7]([NH:25][C@H:26]([C:31]([NH:67][CH2:66][C:65]1[NH:64][N:63]=[N:62][N:61]=1)=[O:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[CH:16]=[C:15]3[CH:20]=[CH:21][CH:22]=[CH:23][C:14]3=[CH:13][C:12]=2[C:11]1=[O:24])([CH3:1])[CH3:34]
Reactant: NCc1nnn[nH]1
Reactant: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: NC(=O)CCC(=O)NO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2cc3ccccc3cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1nnn[nH]1
Reaction time: 1 h

Procedure:
50 mg of N-[(R)-1-[(1,1-dimethylethoxy)carbonyl]-3-(1,3-dihydro-1,3-dioxo-2H-benz[f]isoindol-2-yl)propyl]-L-leucine, prepared as in Example L, was added to of 40 mg N-hydroxysuccinamide in 5 mL DMF. 150 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for 1 h. 43 mg of (1H-Tetrazol-5-ylmethyl)amine dihydrochloride was added followed by 1 mL triethylamine. The mixture was stirred for 18 h, filtered through celite, and the solvents removed by evaporation. The resulting residue was purified by reverse phase H.P.L.C. to give the title compound as a white solid; 18 mg.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH3:26]>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Reactant: Cc1cc(C#N)sc1Br
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C1(CCCCC1)OC(C)N2

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 5-bromo-4-methyl-2-thiophenecarbonitrile. A brown solid: 1H-NMR (DMSO-d6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8 Hz), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=8.2 Hz), 4.74 (r, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 (d, 3H, J=5.3 Hz); MS (ESI) m/z 337 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([OH:30])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:10][CH:9]=2)[CH:7]=1.Cl[CH2:34][O:35][C:36](=[O:46])[C@@H:37]([NH:41][C:42]([O:44][CH3:45])=[O:43])[CH:38]([CH3:40])[CH3:39].[Na+].[I-].N1C=CC=CC=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH2:26][C@@H:27]([OH:31])[C:28]([O:30][CH2:34][O:35][C:36](=[O:46])[C@@H:37]([NH:41][C:42]([O:44][CH3:45])=[O:43])[CH:38]([CH3:40])[CH3:39])=[O:29])[NH:16][C:17]([C:19]3[O:23][N:22]=[C:21]([O:24][CH3:25])[CH:20]=3)=[O:18])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)OCCl)C(C)C
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (200 mg, 430 mmol), (S)-2-methoxycarbonylamino-3-methylbutyric acid chloromethyl ester (193 mg, 860 mmol), NaI (129 mg, 860 μmol) and pyridine (136 mg, 1.7 mmol) in DMF (5.0 mL) was stirred at 25° C. overnight. The mixture was then poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (PE:EtOAc=1:1) to yield the title compound as a colorless liquid (7 mg). LC-MS: 651.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 0.95-0.97 (m, 6H), 2.06-2.14 (m, 1H), 3.34-3.39 (m, 2H), 3.69 (s, 3H), 3.98 (s, 3H), 4.08-4.11 (m, 1H), 4.22-4.24 (m, 2H), 4.38-4.40 (m, 1H), 5.78-5.91 (m, 2H), 6.54 (s, 1H), 7.18-7.22 (m, 1H), 7.34-7.36 (m, 1H), 7.46-7.55 (m, 5H).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:13])[C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:14](O)(=O)[C:15](C)([CH3:17])[CH3:16].S(O[O-])([O-])(=O)=O>C(#N)C.O.C(OCC)C.[N+]([O-])([O-])=O.[Ag+]>[C:15]([C:11]1[C:10](=[O:12])[C:9]2[C:4]([C:3](=[O:13])[C:2]=1[OH:1])=[CH:5][CH:6]=[CH:7][CH:8]=2)([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)C(=O)O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])O[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)C1=C(O)C(=O)c2ccccc2C1=O
Temperature: 20 °C
Yield: 34.4 %

Procedure:
2-Hydroxynaphthalene-1,4-dione (1.00 g, 5.68 mmol), pivalic acid (870 mg, 8.51 mmol) and silver nitrate (568 mg) were heated in a mixture of acetonitrile (20 ml) and water (20 ml) at 60-65° C. A solution of animonium peroxysulphate (1.94 g, 8.51 mmol) in water (10 ml) was added dropwise and the mixture heated for 1 hour. The mixture was then cooled to room temperature (about 20° C.), diluted with diethyl ether and extracted with 1% (w/v) aqueous sodium hydroxide solution (4×25 ml). The combined aqueous layers were then acidified with 2M hydrochloric acid and extracted with diethyl ether (3×25 ml). The combined ethereal extracts were then washed with water and saturated sodium chloride solution and dried over magnesium sulphate. Filtration and evaporation of the solvent under reduced pressure and purification by silica gel column chromatography yielded 2-(t-butyl)-3-hydroxynaphthalene-1,4-dione (450 mg) as a yellow crystalline solid, m.pt.: 89° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C[C@@H](N)CO
Solvent: C1CCOC1
Product: CC(C)C[C@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of D-(−)-leucinol (2.0 g, 17.1 mmol) in THF (30 mL) was slowly added 1,3-propanesultone (1.94 g, 16.3 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH (240 mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (2.55 g, (65%). 1H NMR (D2O, 500 MHz) δ ppm 3.74 (d, 1H, J=12.7 Hz), 3.56 (d, 1H, J=12.7 Hz), 3.20 (m, 1H), 3.10 (t, 2H, J=7.3 Hz), 2.87 (t, 2H, J=7.3 Hz), 2.00 (m, 2H), 1.49 (m, 2H), 1.31 (m, 1H), 0.80 (d, 3H, J=6.3 Hz), 0.76 (d, 3H, J=6.3 Hz). 13C (D2O, 125 MHz) δ ppm 58.74, 58.01, 48.19, 43.56, 35.98, 24.34, 22.54, 21.63, 20.90. [α]D=−16.3° (c=0.0019 in water), ES-MS 238 (M−1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8](=N)[NH2:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[NH3:12].[OH2:13]>[O-]S([O-])(=O)=O.[Cu+2]>[NH2:12][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:13])[CH:5]=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc(C(=N)N)nc1Br
Reactant: O
Reactant: N
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: Cc1ccc(C(N)=O)nc1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL sealed tube, was placed a solution of 6-bromo-5-methylpicolinimidamide (compound 350.3, 800 mg, 3.74 mmol, 1.00 equiv) and CuSO4 (80 mg) in NH3.H2O (40 mL). The resulting mixture was stirred overnight at 80° C. behind a blast shield. After cooling to ambient temperature, the mixture was then extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 750 mg (crude) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=2)[C:25]1=[O:43]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:29]3[CH:30]=[C:31]4[C:26](=[CH:27][CH:28]=3)[C:25](=[O:43])[N:24]([CH3:23])[CH2:33][CH2:32]4)[C:16]2=[CH:15][N:14]=1
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCN(C)C5=O)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 8, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one. LCMS (M+H)+=484.1/486.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH:18]=O)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]1([CH2:17][CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: O=CC[C@@]1(c2ccccn2)CCOC2(CCCC2)C1
Reactant: NCCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc([C@]2(CCNCCc3cccnc3)CCOC3(CCCC3)C2)nc1
Reaction time: 8 h

Procedure:
To a solution of 2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]acetaldehyde (50 mg, 0.19 mmole), 5 mL DCM and NA2SO4 (134 mg, 0.95 mmole) was added 2-(pyridin-3-yl)ethan-1-amine (31 mg, 0.25 mmole) and the reaction was stirred overnight. NaBH4 (9.5 mg, 0.25 mmole) added, stir 10 minutes, 2 drops MeOH added, stir 1 h, quenched with water, organics separated off and evaporated. The residue was passed through a Gilson reverse phase HPLC to give {2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl}[2-(pyridin-3-yl)ethyl]amine, 65.3 mg (71%). LCMS m/z 367.1 (M+1) observed.
Reaction SMILES: B.[O:2]1[CH2:6][CH2:5]CC1.[C:7]1([C:13]2(/[CH:23]=[CH:24]/[CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[CH2:22][CH2:21][C:16]3([O:20][CH2:19][CH2:18][O:17]3)[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-:40].[Na+].OO>O>[C:6]([O:2][CH:23]([C:13]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)[CH2:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)(=[O:40])[CH3:5]
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: FC(F)(F)c1cc(C/C=C/C2(c3ccccc3)CCC3(CC2)OCCO3)cc(C(F)(F)F)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1(c2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Borane-tetrahydrofuran complex (1.0M in tetrahydrofuran, 12 mL, 12 mmol) was added over 10 minutes to a solution of (E)-8-phenyl-8-{3-[3,5-bis(trifluoromethyl)phenyl]prop-1-enyl}1,4-dioxaspiro[4.5]decane (Description 35, 1.88 g, 4 mmol) and the mixture was stirred at room temperature for 4.5 hours. Water (2 mL) then aqueous sodium hydroxide (4M, 20 mL) and aqueous hydrogen peroxide (30 w/v %, 20 mL) were added and the mixture was stirred at room temperature for 30 minutes. Water (150 mL) was added and the mixture was extracted with ether (2×150 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (10 mL) and 4-dimethylaminopyridine (10 mg) and acetic anhydride (5 mL) were added. The mixture was stirred at room temperature for 4 hours, then water (150 mL) was added. The mixture was extracted with ethyl acetate (2×150 mL) and the combined organic fractions were washed with water (2×150 mL) and aqueous copper sulfate (5%, 2×100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2/EtOAc (99:1 increasing to 95:5), to give:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[CH2:20][CH:19]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)[O:18][C:15]3=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:30][OH:31]>>[OH:31][NH:30][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH:19]2[O:18][C:15]3=[CH:16][N:17]=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=4)[CH:13]=[C:14]3[CH2:20]2)[CH2:22][CH2:23]1)=[NH:28]
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C#N)CC2)C3)cc1
Reactant: NO
Agent: Cl
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(C(=N)NO)CC2)C3)cc1

Procedure:
The title compound is prepared from 4-[5-(4-methanesulfonylmethyl-phenyl)-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile and hydroxylamine hydrochloride following a procedure analogous to that described for Intermediate 11. LC (method 5): tR=0.83 min; Mass spectrum (ESI+): m/z=431 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:36])[C:32](=[O:35])[CH2:33][OH:34])[CH3:30])[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[OH:15]>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][C@H:29]([N:31]([CH3:36])[C:32](=[O:35])[CH2:33][OH:34])[CH3:30])[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1
Reactant: ClCc1cscn1
Reactant: C[C@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 64 %

Procedure:
The procedure described in Example 3 was repeated using 4-(chloromethyl)-1,3-thiazole and N-[(1R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide (obtained as described in Example 54, preparation of starting materials) to give the title compound as a white solid in 64% yield; NMR spectrum (DMSO-d6 373K) 1.25 (d, 3H), 2.83 (s, 3H), 3.98 (s, 2H), 4.34 (m, 1H), 4.47 (t, 1H), 4.98 (m, 1H), 5.34 (s, 2H), 7.19 (d, 1H), 7.37 (d, 2H), 7.51 (dd, 1H), 7.70 (t, 1H), 7.74 (d, 1H), 7.93 (d, 1H), 8.46 (s, 1H), 9.08 (s, 1H), 9.57 (s, 1H); Mass spectrum MH+ 514.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:24]([O:31][C:32]([NH:34][C:35]([CH3:42])([CH3:41])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:38](=[O:39])[CH2:37][CH2:36][C:35]([NH:34][C:32]([O:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])([CH3:42])[CH3:41])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Reactant: CC(C)(CCC(=O)O)NC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
D-Homophenylalanine allyl ester (175 mg; 0.80 mmol) (see Example 9, Step B), triethylamine (222 μl; 1.59 mmol) were dissolved in dry methylene chloride (2 ml) and 4-(benzyloxycarbonylamino)-4-methyl-pentanoic acid (211 mg; 0.80 mmol) added. The solution was stirred at room temperature and BOP (353 mg; 0.80 mmol) was added over 5 minutes, and this reaction mixture stirred at room temperature for 17 h. The reaction was quenched by adding brine and then the products of the reaction isolated by extraction with methylene chloride (3×15 ml). The methylene chloride layers were combined and dried with anhydrous magnesium sulfate powder, filtered and evaporated under reduced pressure. A thick golden yellow gum was obtained which was purified by column chromatography on silica gel using ethyl acetate and hexanes 1:2 v/v. The product (182 mg; 48.9%) was isolated as a pale yellow gum. FAB-MS:- calculated for C27H34 N2O5 466.3; found 467.7 (M+1).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=N.C[N:14](C=O)C.[C:18]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19]1>CN(C1C=CC=CN=1)C.N1C=CC=CC=1>[NH2:14][N:9]=[CH:7][C:6]1[CH:5]=[C:4]([NH:3][CH:21]([CH:22]=[O:23])[CH2:20][CH2:19][C:18]([OH:24])=[O:25])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCC(=O)O1
Reactant: N=C(N)c1cccc(N)c1
Reactant: CN(C)C=O
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Product: NN=Cc1cccc(NC(C=O)CCC(=O)O)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
3-Aminobenzamidine di-HCL (5 g, 24 mmol) was added to dry DMF (30 mL). To this solution dry pyridine (5 mL) and glutaric anhydride (3.0 g, 26 mmol), followed by 10 mg dimethylaminopyridine (DMAP) were added. The product was heated for 3 h at 100° C. and allowed to stir at room temperature for 16 h. Solvents were removed in vacuo, water was added to the residue and the pH was brought to a value of 6.8 using dilute sodium hydroxide. An abundant precipitate was filtered, washed with water followed by ethyl acetate. The white solid was filtered and dried in a desiccator to give 5.4 g, 90% of product as a white solid: 1H NMR (d6 -DMSO) δ 1.8 (m, 2H), 2.3 (m, 2H), 2.45 (m, 2H), 7.6 (d, 1H, J=8 Hz), 7.55 (dd, 1H, J=8 Hz and J= 7.5 Hz), 7.85 (d, 1H, J=7.5 Hz), 8.05 (s, 1H), 9.05 (bs, 2H), 9.25 (bs, 2H), 10.4 (s, 1H); MS (FAB) m/e 250.1 (MH+).
Reaction SMILES: [BrH:1].[OH-].[Na+].[CH3:4][CH:5]([CH2:7][C@@H:8]1[N:17]2[C:18]([C@@:20]([NH:25][C:26]([C@@H:28]3[CH:43]=[C:42]4[C@@H:31]([CH2:32][C:33]5[C:37]6[C:38]4=[CH:39][CH:40]=[CH:41][C:36]=6[NH:35][CH:34]=5)[N:30]([CH3:44])[CH2:29]3)=[O:27])([CH:22]([CH3:24])[CH3:23])[O:21][C@@:16]2([OH:45])[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:10])=[O:19])[CH3:6].[OH-].[NH4+]>CS(C)=O.ClCCl.O>[CH3:6][CH:5]([CH2:7][C@@H:8]1[N:17]2[C:18]([C@@:20]([NH:25][C:26]([C@@H:28]3[CH:43]=[C:42]4[C@@H:31]([CH2:32][C:33]5[C:37]6[C:36](=[CH:41][CH:40]=[CH:39][C:38]=64)[NH:35][C:34]=5[Br:1])[N:30]([CH3:44])[CH2:29]3)=[O:27])([CH:22]([CH3:23])[CH3:24])[O:21][C@@:16]2([OH:45])[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:10])=[O:19])[CH3:4]
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Reactant: Br
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Dry gaseous hydrogen bromide is introduced to 70 ml. of anhydrous dimethylsulphoxide at room temperature. The amount of the introduced hydrogen bromide is measured by titrating against 0.1N sodium hydroxide solution. The hydrogen bromide is introduced until reaching a hydrogen bromide content of 0.0003 to 0.0005 mole/ml. in the dimethylsulphoxide. Then 10 g (0.01737 mole) of α-ergocryptine are dissolved in an amount containing 12 equivalents of hydrogen bromide as taken out from the thus-obtained mixture containing hydrogen bromide in dimethylsulphoxide. The reaction mixture is stirred at room temperature for 15 minutes beginning from the complete dissolution of α-ergocryptine, then poured in 5 volumes of water as calculated for the volume of dimethylsulphoxide. Then the mixture is alkalinized to a pH value of 8 to 9 by adding ammonium hydroxide, the precipitated 2-bromo-α-ergocryptine is filtered off, washed twice with 10 ml. of water each, dissolved in 200 ml. of dichloromethane and dried over anhydrous sodium sulphate. After filtering off the drying agent, 200 ml. of diisopropyl ether are added to the solution and dichloromethane is distilled off under atmospheric pressure. 2-bromo-αergocryptine separated from the distillation residue is filtered off and washed to give a yield of 8.4 g. (74%), m. p.: 215°-217° C., [α]D20 =-190° c=1%, dichloromethane).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[OH:25]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH2:17])=[C:19]([O:25][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=2)[CH:20]=1
Reactant: CCS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Reactant: Nc1ccc(Cl)cc1O
Product: CCS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)cc1C(F)(F)F

Procedure:
The subtitle compound was prepared by the example 3 step viii) using the product from example 22 step i) and 2-amino-5-chlorophenol. Yield 11.0 g