Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH3:2].Cl.N1C=CC=CC=1.CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=1)[CH3:2]
Reactant: CCOCC(=O)Nc1cnc2ccccc2c1NN1CCOCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1N1CCOCC1
Reaction time: 60 h
Yield: 31.8 %

Procedure:
A suspension of 2-ethoxy-N-{4-[(morpholin-4-yl)amino]quinolin-3-yl}acetamide (5.35 g, 16.2 mmol) in 65 mL of toluene was treated with pyridine hydrochloride (0.94 g g, 0.081 mmol). The reaction flask was equipped with a Dean-Stark trap and the reaction mixture was heated to reflux under an atmosphere of nitrogen. After 2.5 d, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was dissolved in CHCl3 and was washed with 5% Na2CO3 solution, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to yield a brown foam. Chromatography (SiO2, 95:5 CHCl3:MeOH) gave 2-ethoxymethyl-1-(morpholin-4-yl)-1H-imidazo[4,5-c]quinoline (1.61 g) as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[C:6]([O:13][CH2:14][CH2:15][CH2:16]Cl)=[CH:5][C:4]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21])#[N:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH2:8][C:7]([O:11][CH3:12])([O:9][CH3:10])[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:5][C:4]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21])#[N:2]
Reactant: COC1(OC)CC(C#N)=C(N=CN(C)C)C=C1OCCCCl
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC1(OC)CC(C#N)=C(N=CN(C)C)C=C1OCCCN1CCCCC1
Yield: 92.4 %

Procedure:
N′-(2-cyano-4-methoxy-5-(3-chloropropoxy)4-methoxyphenyl)-N,N-dimethylimidoformamide (3 g, 10 mmol) in acetonitrile (50 ml) was reacted with piperidine (10 ml, 100 mmol) in presence of KI (300 mg, 1.8 mmol) and K2CO3 (2.1 g, 0.015 mmol) at 75° C. under argon for 3 hours. The solvent was evaporated, and the residue purified by silica gel chromatography, Eluant CH2Cl2/MeOH, NH3 3N 95/5 to give title compound (3.48 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][CH:54]=[CH:53][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][CH2:41]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[C-:57]#[N:58].[K+]>CN(C)C=O.[OH-].[Na+]>[C:57]([CH2:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:53]=[CH:54][CH:55]=[CH:56][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19]1)#[N:58]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCC#N)cc1
Temperature: 25 °C

Procedure:
A solution of 0.20 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}ethoxy)piperidine-1-carboxylate (Example 26b) and 0.33 g of potassium cyanide in 4 ml of N,N-dimethylformamide is stirred at 65° C. over 10 hours. The reaction mixture is cooled to room temperature, diluted with 0.1N NaOH and extracted with tert-butyl methyl ether (2×) and ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.44 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH:9]([OH:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:18]I>O>[C:9]([C:4]1[N:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([I:18])[CH:5]=1)(=[O:11])[CH3:10]
Reactant: CC(O)c1ccc(O)c(Cl)n1
Reactant: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)c1cc(I)c(O)c(Cl)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
2-Chloro-3-hydroxy-6-(1-hydroxyethyl)pyridine (7.19 g, 41.4 mmole) was dissolved in 80 ml of water containing potassium carbonate (17.2 g, 124 mmole) in a 200 ml one neck round bottom flask. The solution was treated with iodine (31.5 g, 124 mmole) and was stirred for 6 h at room temperature. The mixture was quenched with saturated sodium thiosulfate and the pH was adjusted to 2 with 12 N hydrochloric acid. The precipitate was collected, was washed with water, and was dried. The yellow solid was further washed with diethyl ether to provide 4.68 g (38%) of 6-acetyl-2-chloro-3-hydroxy-4-iodo-pyridine as a pale tan solid (Melting Point: 223-224° C.).
Reaction SMILES: ClC1C=CC2N([CH:11]3[CH2:14][O:13][CH2:12]3)C(CCl)=NC=2C=1.[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([C@@H:39]3CCS(=O)(=O)[CH2:40]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1.CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:17][C:18]1[CH:47]=[CH:46][C:21]2[N:22]([CH2:39][CH2:40][CH:11]3[CH2:14][O:13][CH2:12]3)[C:23]([CH2:25][N:26]3[C:30]4=[CH:31][N:32]=[CH:33][CH:34]=[C:29]4[C:28]([S:35]([CH3:38])(=[O:37])=[O:36])=[N:27]3)=[N:24][C:20]=2[CH:19]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCS(=O)(=O)C2)c2cnccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCC2COC2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole (Example 2-1) instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:11][NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]=O>O.C1(C)C=CC=CC=1>[CH2:4]([O:11][N:12]=[CH2:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=O
Reactant: NOCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00 g, 31.32 mmol) and formaldehyde (˜37 wt. % in H2O) (2.3 mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, the organic phase was separated and the water phase was extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to yield formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz 1H NMR (CDCl3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47 (1H, d, J=8.2 Hz), 5.14 (2H, s).
Reaction SMILES: C[C:2]1[C:16]([C:17](O)=[O:18])=[CH:15][C:5]2[N:6]([CH3:14])[C:7]([CH2:9][C:10]([OH:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.Cl.[CH3:28][C:29]1[N:33]=[C:32]([C@H:34]([NH2:36])[CH3:35])[O:31][N:30]=1.ON1C2N=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:3]2[C:4]3[N:8]=[C:7]([CH2:9][C:10]([OH:13])([CH3:11])[CH3:12])[N:6]([CH3:14])[C:5]=3[CH:15]=[C:16]([C:17]([NH:36][C@@H:34]([C:32]3[O:31][N:30]=[C:29]([CH3:28])[N:33]=3)[CH3:35])=[O:18])[CH:2]=2)=[CH:25][CH:24]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: Cc1c(C(=O)O)cc2c(nc(CC(C)(C)O)n2C)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c3nc(CC(C)(C)O)n(C)c3c2)n1
Temperature: 50 °C
Yield: 82 %

Procedure:
To a mixture of methyl 4-(4-fluorophenyl)-2-(2-hydroxy-2-methylpropyl)-1-methyl-1H-benzimidazole-6-carboxylic acid (122 mg, 0.236 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine hydrochloride (46.3 mg, 0.283 mmol), 1-hydroxy-7-azabenzotriazol (3.21 mg, 0.024 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (79 mg, 0.412 mmol) was added DMF (0.471 mL) followed by triethylamine (0.099 mL, 0.707 mmol). Reaction heated at 50° C. for 30 min. Reaction cooled and filtered. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% TFA) gave the title compound (87.4 mg): LC-MS [M+1]=452.4; 1H NMR (500 MHz, CHCl3-d): δ 7.94 (2H, m), 7.90 (1H, s), 7.77 (1H, s), 7.20 (1H, d, J=7.73 Hz), 7.15 (2H, t, J=8.51 Hz), 5.66-5.59 (1H, m), 5.47 (1H, s), 3.78 (3H, s), 3.02 (2H, s), 2.39 (3H, s), 1.74 (5H, d, J=7.14 Hz), 1.35 (6H, s).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:41])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][C:28]3[C:37]4[C:32](=[C:33]([C:38](=[O:40])[NH2:39])[CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][N:29]=3)[CH:21]=2)[CH:13]=1)C)(C)(C)C.Cl>O1CCOCC1>[CH3:6][NH:7][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[C:18]([NH:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[CH2:26][NH:27][C:28]1[C:37]2[C:32](=[C:33]([C:38]([NH2:39])=[O:40])[CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][N:29]=1)=[O:41]
Reactant: CN(CCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCOc1cccc(C(=O)Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1
Reaction time: 8 h

Procedure:
12 mg (0.11 mmol [2-(3-{3-[(8-Carbamoyl-quinazolin-4-ylamino)-methyl]-phenylcarbamoyl}-phenoxy)-ethyl]-methyl-carbamic acid tert-butyl ester were dissolved in 2 ml dioxane and 88 μl 4 N HCl in dioxane were added. The mixture was stirred overnight, filtered and washed with dioxane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 50.0 mg, 0.168 mmol), 0.50 mL of pyridine was added, followed by addition of N,N-dimethylamino-sulfonyl chloride (32, 54 μL, 0.51 mmol) and the solution was stirred at room temperature for 2 days. The reaction mixture was extracted with 1 M aqueous hydrochloric acid and with ethyl acetate. The organic layer was washed with water, then brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0007, 28 mg). MS(ESI)[M+H+]+=405.8.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl>CCO.[OH-].[OH-].[Pd+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:10]([C@@H:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:9][OH:8])=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(Cl)ccc1O[C@@H](COCc1ccccc1)[C@H]1CCNC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1cc(Cl)ccc1O[C@H](CO)[C@@H]1CCNC1

Procedure:
To a solution of (S)-3-[(R)-2-benzyloxy-1-(4-chloro-2-methylphenoxy)ethyl]-pyrrolidine•TFA (4.6 mg, 10 μmol) in EtOH (2.0 mL) at room temperature, was added concentrated HCl (˜50 μL). To the stirred mixture was added 20% Pd(OH)2/C (50 wt % water, 4.0 mg). The resulting mixture was degassed and flushed with hydrogen three times and then hydrogenated under a hydrogen balloon for 25 minutes. The mixture was filtered and the filtrate was concentrated. The resulting residue was redissolved in a mixture of AcOH (0.5 mL) and water (1.0 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, 98% purity). MS m/z: [M+H]+ calcd for C13H18ClNO2, 256.10; found 256.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[C:15]([C:19]2[S:23][C:22]([NH2:24])=[N:21][N:20]=2)=[C:14]([F:25])[CH:13]=1>C1COCC1>[CH2:3]([O:10][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([F:25])[C:15]=1[C:19]1[S:23][C:22]([NH2:24])=[N:21][N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: Nc1nnc(-c2c(F)cc(Br)cc2F)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nnc(-c2c(F)cc(Br)cc2OCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
A stirred suspension of NaH (60% dispersion in mineral oil, 151 mg, 3.77 mmol) in THF (10 mL) was cooled under nitrogen in an ice bath. To this suspension was added a solution of benzyl alcohol (0.372 mL, 3.59 mmol) in THF (5 mL) drop-wise. On completion of addition, the resulting suspension was stirred at ice bath temperature for 5 minutes, then room temperature for 10 minutes, before being slowly added to a stirred, ice-bath cooled suspension of 5-(4-bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine (1 g, 3.42 mmol) in THF (20 mL). The resulting yellow/brown suspension was stirred at ice bath temperature for 15 minutes, room temperature for 1 hour then heated at 50° C. for 18 hours. The reaction was quenched by addition of saturated NH4Cl(aq) (30 mL), diluted with water (30 mL), and extracted with EtOAc (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated onto silica gel and the crude material was purified by flash chromatography using an 80 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow solid (488 mg, 37% yield). LC-MS: Rt 1.19 min; MS m/z 282.0 M+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.47 (m, 9H), 5.28 (s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (22 mg, 0.045 mmol) in DCM (4 mL) was added TFA (1 mL). The mixture was stirred at RT for 1 h and then directly loaded onto an SCX cartridge (2 g, pre-wet using DCM). Impurities were removed by eluting with MeOH:DCM (1:1) and product eluted using NH3 solution (2M in MeOH):DCM (1:1) to give the title compound (14 mg, 82%). LCMS (Method F): RT=9.03 min, [M+H]+=386. 1H NMR (400 MHz, CDCl3): δ 7.92 (dd, J=8.3 and 3.2 Hz, 1H), 7.55 (dd, J=9.5 and 4.7 Hz, 1H), 7.47-7.32 (m, 6H), 7.29 (d, J=7.9 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 2.61-2.50 (m, 2H), 2.22-2.00 (m, 3H), 1.82-1.69 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH:13][CH:14]1[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]([CH3:12])[CH:14]1[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18]1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CNC1CCN(C)C1
Solvent: CCOC(C)=O
Product: CN1CCC(N(C)c2ccc([N+](=O)[O-])cc2Cl)C1
Reaction time: 24 h

Procedure:
3-Chloro-4-fluoronitrobenzene (1.0 g) and N,N′-dimethyl-3-aminopyrrolidine (1.72 g) are combined and stirred for approximately 24 hours. The mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride, and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue is chromatographed over silica gel (pure ethyl acetate followed by pure methanol is used as the eluants) to provide the desired product as a yellow oil. p Using the above procedure and appropriate starting materials the following compounds were prepared:
Reaction SMILES: NC1C=CC(F)=CC=1[C:4](N(OC)C)=[O:5].C([Mg]Cl)(C)C.[CH3:20][C:21]1[C:22]([Mg]Br)=[N:23][CH:24]=[CH:25][CH:26]=1>C1COCC1>[CH3:20][C:21]1[C:22]([CH:4]=[O:5])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: CON(C)C(=O)c1cc(F)ccc1N
Reactant: Cc1cccnc1[Mg]Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cccnc1C=O
Reaction time: 0.67 h

Procedure:
To a solution of 2-amino-5-fluoro-N-methoxy-N-methylbenzamide (1.0 g, 5.05 mmol) in THF (4.2 mL) was added isopropylmagnesium chloride (2.0M in THF, 5.0 mL, 10.1 mmol) at −40° C. The temperature was allowed to rise to −10° C. over 40 min then was lowered to −40° C. in an acetonitrile/dry ice bath. 3-Methyl-2-pyridinylmagnesium bromide (0.25M in THF, 20.2 mL, 5.0 mmol) was added dropwise and the solution was allowed to rise to rt over one hour. The solution was partitioned between satd ammonium chloride solution and DCM; organic extracts were concentrated then purified by silica gel column chromatography eluting with a gradient of 10-70% EtOAc in hexane to afford 2-amino-5-fluorophenyl)(3-methylpyridin-2-yl)methanone as a yellow oil: LC-MS (ESI) m/z 231.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][CH2:25][CH2:26][OH:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH2:26][OH:27]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CCCO
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 355 mg, 1.17 mmol), tetrabutylammonium iodide (220 mg, 0.60 mmol) and 3-bromo-1-propanol (450 μL, 5.0 mmol) in dimethylformamide (4 mL) was heated at 100° C. for 21 h. Dichloromethane (100 mL), and the solution was washed with aqueous sodium thiosulfate (25 mL), and water (4×25 mL). The solution was dried (magnesium sulfate), and filtered. Silica gel was added and the solvent was evaporated. The resulting material was purified using an ISCO 12 g column, eluting with 0-5% methanol/ethyl acetate. Fractions containing the product were combined, evaporated, and dried under high vacuum at 95° C. overnight to give a gum that solidified on scratching. In this way was obtained (4S,7R)-2-(2,4-difluoro-phenyl)-1-(3-hydroxy-propyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (21 mg, 9%) as a light brown solid. APCI(+)-MS (M+H) 363.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)=[CH:11][CH:10]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13](=[N:24][OH:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: NO
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(C(=NO)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (compound 101, 0.58 g, 2 mmol) and hydroxylamine hydrochloride (0.42 g, 6 mmol) in ethanol (30 ml) was added sodium acetate (0.49 g, 6 mmol). The reaction mixture was refluxed for 30 hours, cooled to room temperature, filtered, and evaporated in vacuo. The residue was treated with water (10 ml) and diluted ammonium hydroxide (5 ml). The precipitate that forms was filtered off, washed with water and dried to afford the title compound.
Reaction SMILES: [CH3:1][C:2](=C)[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C(N(CC)CC)C>C(Cl)Cl>[C:8]1([CH:7]([O:6][C:4](=[O:5])[C:3]([N:20]2[C:26](=[O:27])[C@H:25]3[C@@H:21]2[O:22][C:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:24]3)=[CH:2][CH3:1])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(Cc3ccccc3)O[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(Cc3ccccc3)O[C@@H]21
Yield: 95 %

Procedure:
In a manner similar to the above (1), a solution of 75 mg of diphenylmethyl (2R)-3-methyl-2-[(1R,5S)-3-benzyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-3-butenoate in 5 ml of methylene chloride is stirred at room temperature for 1 hour in the presence of 0.03 ml of triethylamine to afford diphenylmethyl-2-[(1R,5S)-3-benzyl-7-oxo-4-oxa-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-2-butenoate in 95% yield. mp. 104.5°-106° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:32](Br)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Br)c1ccccc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccccc4)cc3)ccc2C1=O
Reaction time: 0.08 h

Procedure:
To a solution of compound of example 223 (100 mg, 0.295 mmol) in dichloromethane (3 mL), pyridine (70.53 mg, 0.885 mmol) was added and stirred for 5 min followed by addition of benzoyl bromide (81.96 mg, 0.443 mmol). The reaction mixture was stirred for about 16 h. After completion of the reaction, the solvent was evaporated to obtain the title compound, which was directly used for the preparation of compound of example 305.