Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[C:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])(=O)[CH3:6].CC1C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:6][C:5]1([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[O:4][CH2:1][CH2:2][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(C#N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: 110 °C
Yield: 75.9 %

Procedure:
To the mixture of ethylene glycol (0.22 mL, 4 mmol), 3-acetylbenzonitrile 18 (300 mg, 2.04 mmol) and benzene (10 mL) in a Dean-Stark apparatus was added a catalytic amount of p-TSA (0.1 equiv). The reaction mixture was heated at 110° C. for 4 h. The benzene was removed under reduced pressure and the residue was purified by column chromatography using ethylacetate-hexane as an eluent to give 19 (293 mg, 76%). 1H NMR (CDCl3, 400 MHz) δ 2.62 (s, 4H), 7.59 (t, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H)), 8.15 (d, J=8 Hz, 1H), 8.21 (s, 1H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:28].[K+]>O>[F:11][C:10]([F:13])([F:12])[C:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[I:28])([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: [I-]
Reactant: Cc1ccc(N)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cc1ccc(I)c(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
To compound 1 (2 g, 7.32 mmol) in suspension in distilled water (20 mL) cooled in a ice-bath was added sulfuric acid (0.5 mL). Sodium nitrite (505 mg, 7.32 mmol) dissolved in water (2.5 mL) was added dropwise and another 0.5 mL sulfuric acid was added. The mixture was stirred at 0° C. until complete dissolution of the suspension (ca 30 min). The solution was added dropwise over 30 min to ice cooled potassium iodide (1.46 g, 8.78 mmol) dissolved in distilled water (5 mL). The reaction mixture when then heated at 80° C. until nitrogen formation stops (ca 30 min). After return to room temperature, the red suspension was filtered, washed with water and dissolved in diethylether (50 mL). It was washed with water (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was chromatographied on a silica gel column with heptane/chloroform (1/1) as eluent to give 1.98 g (5.16 mmol, 71% yield) of a yellow oil which solidifies at 4° C. over night.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11](I)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:10][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[F:20])=[C:12]([Cl:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1F
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(-c2ccccc2F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example 1) (30 g, 75.3 mmol) and 2-fluorophenylboronic acid (13.82 g, 98.8 mmol) according to the general procedure D. Obtained as a yellow gum (1.39 g).
Reaction SMILES: [NH:1]=[C:2]1[CH:11]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([C:20]2[CH:25]=[C:24]3[O:26][CH2:27][O:28][C:23]3=[C:22]([O:29][CH3:30])[CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([N:31]([CH3:33])[CH3:32])=[CH:7][CH:8]=2)[O:3]1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:20]3[CH:25]=[C:24]4[O:26][CH2:27][O:28][C:23]4=[C:22]([O:29][CH3:30])[CH:21]=3)[C:11]=1[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[CH:8][CH:7]=[C:6]([N:31]([CH3:32])[CH3:33])[CH:5]=2
Reactant: COc1cc(C2c3ccc(N(C)C)cc3OC(=N)C2C(=O)c2ccccc2)cc2c1OCO2
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(C2C(C(=O)c3ccccc3)=C(N)Oc3cc(N(C)C)ccc32)cc2c1OCO2
Yield: 68.6 %

Procedure:
A solution of 2-imino-3-benzoyl-7-dimethylamino-4-(3-methoxy-4,5-methylenedioxyphenyl)-chromane (26 mg, 0.059 mmol) and triethylamine (0.1 ml) in ethanol (5 ml) was refluxed for 12 h. It was concentrated, and the residue was purified by column chromatography (silica gel, EtOAc/Hexane=1:5) to give 18 mg (72%) of the title compound. 1H NMR (CDCl3): 7.40-7.30 (m, 2H), 7.18-7.14 (m, 2H), 6.86 (d, 1H), 6.50-6.34 (m, 2H), 6.00 (d, 1H), 5.85-5.81 (m, 2H), 5.73 (d, 1H), 4.73 (s, 1H), 3.67 (s, 3H), 2.91 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][CH:3]=1.[NH2:19][OH:20].Cl>C(N(CC)CC)C>[OH:20][NH:19][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=C(O)CCCCCCC(=O)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC(=O)c1ccc(Br)cc1)NO
Yield: 31 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 50d for 37 and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound was obtained as light yellow solid in 31% yield: 1H NMR (300 MHz, CD3OD/CDCl3=5/1) δ 7.82 (d, J=7.5 Hz, 2H), 7.62 (d, J=7.5 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 2.11 (m, 2H), 1.55-1.79 (m, 4H), 1.38 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=[O:12].[CH2:13](O)[CH2:14][OH:15]>C1C=CC=CC=1.C([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: O=Cc1oc2ccccc2c1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Brc1c(C2OCCO2)oc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.5 %

Procedure:
3-bromo-1-benzofuran-2-carbaldehyde (5.49 g, 24.4 mmol) is combined with para-toluene sulfonic acid hydrate (232 mg, 1.2 mmol) and ethylene glycol (2.44 ml, 43.9 mmol) in benzene (75 ml). The reaction is refluxed with a Dean-Stark trap for 5 h. The mixture is cooled to rt and diluted with saturated NaHCO3 solution (20 ml) and left to stir for an additional 12 h. The layers are allowed to separate, and the organic layer is dried over Na2SO4, filtered, and concentrated to afford 6.6 g (100%) of 3-bromo-2-(1,3-dioxolan-2-yl)-1-benzofuran as a dark brown oil. HRMS (FAB) calcd for C11H9BrO3+H: 268.9814, found 268.9821.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[O:10](C(C)=O)[C:11]([CH3:13])=O>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:10])[CH3:13])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)ccc1N
Product: CC(=O)Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 4-fluoro-2-methylaniline (20 g) and (CH3CO)2O (400 mL) was stirred at RT for 3 hours. The reaction mixture was subsequently poured into ice water (1000 mL), stirred for 10 minutes, filtered, and dried under vacuum to give the title compound (20 g, 74%).
Reaction SMILES: [CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH2:19])=O)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O>N1C=CC=CC=1>[CH:1]1([CH2:7][S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]#[N:19])(=[O:9])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#C[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxamide [see Preparation 26], oxalyl chloride, dimethylformamide and pyridine. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:20 changing to 20:80, by volume (in 10% increments), hexane:ethyl acetate to afford (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarbonitrile as an oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=NC=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O.[CH3:28][N:29](C)C=O>O1CCCC1>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:28]2[N:29]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ccc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica eel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS(ESI) [M+H+]+=352.1.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:33][C:34]([O:36][CH2:37][C:38](=[CH2:40])[CH3:39])=[O:35]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(C)=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:33][C:34]([O:36][CH2:37][C:38](=[CH2:39])[CH3:40])=[O:35])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: C=C(C)COC(=O)CCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: C=C(C)COC(=O)COC(=O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Reaction time: 3 h

Procedure:
10 g of indometacin, 4.0 g of potassium carbonate, 0.4 g of benzyltriethylammonium chloride and 60 ml of acetone are stirred for 30 minutes at 56° C. After addition of methallyl chloroacetate, stirring is continued for 3 hours at 40° C. (check by thin layer chromatography).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:29][C:30]1[CH:31]=[C:32]([C:36](=[N:38]O)[NH2:37])[CH:33]=[CH:34][CH:35]=1>>[F:29][C:30]1[CH:31]=[C:32]([C:36]2[N:38]=[C:26]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:27][N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 42.3 mg (0.275 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide (Example 73A) were reacted according to the General Method 1. Yield: 63.9 mg (48% of theory).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8](=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(Cc1ccccc1)C(=O)OCC
Reaction time: 8 h

Procedure:
127.6 g of diethyl 2-benzylmalonate are refluxed with 20.4 g of NaOH in 1 l of dry ethanol. After 8 hours, the solvent is removed, the residue is taken up in 2N HCl, and the solution is extracted with ether. The organic phase is dried and concentrated. The residue is cooled, and 51.2 ml of diethylamine and 43.7 ml of 36% strength formaldehyde solution are added. The mixture is left to stand overnight and then extracted with ether, and the extracts are dried and concentrated. The product is distilled.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:14]=2)=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl>[OH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2ncc(-c3ccccc3)o2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: OCc1ccc(-c2ncc(-c3ccccc3)o2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl-4-(5-phenyloxazol-2-yl)-benzoate (56 mg, 0.19 mmol) in CH2Cl2 (8 mL) at −78° C. was added DIBAL-H (1 mL of a 1.0 M solution in CH2Cl2, 1.0 mmol) and the solution stirred at −78° C. for 90 min. A saturated aqueous solution of sodium potassium tartrate (5 mL) was added to the reaction and the mixture allowed to warm to room temperature. The bi-phasic mixture was stirred rapidly for 60 min, the layers separated and the aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated in vacuo to afford the desired alcohol, 2-(4-hydroxymethylphenyl)-5-phenyloxazole, as a pale yellow oil (46 mg, 96%). 1H NMR (CDCl3) δ 3.41 (t, 1H (OH), J=7.0 Hz), 4.77 (d, 2H, J=7.0 Hz), 7.33 (m, 1H), 7.45 (m, 5H), 7.72 (d, 2H, J=6.4 Hz), 8.08 (d, 2H, J=8.1 Hz).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].FC(C(O)=O)(F)F.C(N(CC)CC)C.C(O)(=O)C.[CH3:56][C:57]([O:60][C:61]([NH:63][CH2:64][C:65](OC1C=CC([N+]([O-])=O)=CC=1)=[O:66])=[O:62])([CH3:59])[CH3:58]>CN(C)C=O.C(OCC)(=O)C>[NH:63]([C:61]([O:60][C:57]([CH3:59])([CH3:58])[CH3:56])=[O:62])[CH2:64][C:65]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([NH:17][C@H:18]([C:21]([NH:23][C@H:24]([C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[C@@H:25]([CH3:27])[OH:26])=[O:22])[CH2:19][OH:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:66]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)OCc1ccccc1)[C@@H](C)O
Temperature: 0 °C
Reaction time: 48 h

Procedure:
26.3 g of H-Asn-Leu-Ser-Thr-OBzl.TFA are dissolved in 100 ml of dimethylformamide, the solution is cooled to 0° C. and successively mixed with 7.5 ml of triethylamine, 0.54 ml of glacial acetic acid and a solution of 14.4 g of BOC-Gly-ONP in 100 ml of dimethylformamide, stirred at room temperature until the mixture solidifies and left to stand for 2 days. Thereafter 300 ml of ethyl acetate are added whilst stirring and the mixture left to stand overnight at -10° C. The precipitate is filtered off, washed twice with ethyl acetate and twice with ether, stirred for half an hour with 200 ml of water, filtered off, washed with water and dried in vacuo. Melting point 227°- 228° C.; [α]D = -23° (c = 2 in dimethylformamide); Rf9 = 0.50 (on silica gel).
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([C@H:25]3[CH2:30][C@@H:29]4[C@@H:27]([CH2:28]4)[N:26]3C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[C@@H:27]12[CH2:28][C@@H:29]1[CH2:30][C@H:25]([C:23]([NH:22][C:19]1([C:16]3[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=3)[CH2:20][CH2:21]1)=[O:24])[NH:26]2
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3)CC2)cc1
Yield: 92.3 %

Procedure:
The title compound (D104) (1.8 g) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from (1R,3R,5R)-tert-butyl 3-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (syn diastereoisomer) (D73a) (2.6 g).
Reaction SMILES: [CH2:1](/[N:8]=[C:9](\[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)/[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[CH2:1]([NH:8][CH:9]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:11])[F:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)/C(=N/Cc1ccccc1)c1ccc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: FC(F)(F)C(NCc1ccccc1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.2 %

Procedure:
To a stirred solution of Benzyl-[1-(5-bromo-pyridin-2-yl)-2,2,2-trifluoro-eth-(E)-ylidene]-amine (0.45 g, 1.31 mmol) in methanol (20 mL) is added sodium triacetoxy borohydride (0.55 g, 2.62 mmol) at 0° C. then stir at room temperature for 3 hours. Reaction mixture is diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 10% ethyl acetate in hexane to afford the title compound (0.15 g). 1H NMR (400 MHz, DMSO-d6) δ: 3.57-3.61 (m, 1H), 3.64-3.73 (m, 2H), 4.50 (m, 1H), 7.22-7.25 (m, 1H), 7.28-7.29 (m, 4H), 7.73 (d, J=8.2 Hz, 1H), 7.91-7.93 (dd, J1=8.2 Hz, J2=2.24 Hz, 1H), 8.48 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=347.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:35]([CH3:37])[CH3:36]>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH:35]([CH3:37])[CH3:36])=[CH:21][C:14]=3[O:13]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C2Oc3cc(O)ccc3C2=O)cc(OC)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=C2Oc3cc(OC(C)C)ccc3C2=O)cc(OC)c1
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 2-[(3,5-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to -obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 316.1 mg.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([NH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([NH:28][C:25](=[O:27])[CH3:26])[CH:30]=[CH:31][CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 25.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-acetamidophenylboronic acid (17.9 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospir-o[chroman-4,4′-imidazole]-6-yl)phenyl)acetamide (5.8 mg, 20%). 1H-NMR (MeOD): 2.03 (s, 3H), 2.21 (t, 1H), 2.41 (t, 1H), 3.07 (s, 3H), 5.81 (d, 1H), 6.92 (d, 1H), 7.12 (t, 1H), 7.21 (t, 2H), 7.33 (t, 2H), 7.49 (m, 4H), 7.59 (d, 1H).
Reaction SMILES: [H-].[Na+].[C:3]12([C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][C:19]([Br:23])=[CH:20]4)=[CH:15][C:14]=3[OH:24])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C.C(O)C>[C:3]12([C:13]3[CH:22]=[C:21]4[C:16]([CH:17]=[CH:18][C:19]([Br:23])=[CH:20]4)=[CH:15][C:14]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:9]3[CH2:11][CH:5]([CH2:6][CH:7]([CH2:8]3)[CH2:12]1)[CH2:4]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reaction time: 2 h

Procedure:
1.26 g (42 mmol) of sodium hydride (80% in oil) and 50 ml of DMF were introduced into a 3-necked flask, a solution of 12.5 g (35 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene in 100 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 5 ml (42 mmol) of benzyl bromide were then added and stirring was carried out at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl ether and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was taken up in ethanol, heated to reflux, cooled, filtered and dried. 12.5 g (80%) of the expected compound were collected, which compound had a melting point of 150°-1° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][C:6]=12.C1C(=O)N([Br:36])C(=O)C1>C(#N)C>[Br:36][C:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:2]=2[F:1])[N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (2.40 g, 5.96 mmol) in 20 mL of acetonitrile at 0° C. was added a solution of NBS (1.01 g, 5.69 mmol, Aldrich) in 10 mL of acetonitrile. The reaction mixture was stirred at 0° C. for 30 min, quenched by the addition of cold water (50 mL), and extracted with EtOAc (3×120 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, eluting with dichloromethane) to afford the desired product (2.70 g, 94%) as a light yellow oil. MS(ESI+) m/z 482.9 (M+H)+.