Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[NH:15][C:14]1=[O:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][C:13]1([CH3:20])[NH:17][C:16](=[O:18])[N:15]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=2)[C:14]1=[O:19]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC1(C)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2C(=O)NC(C)(C)C2=O)ccc1[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (1.55 g, 10 mmoles), 5,5-dimethylhydantoin (1.28 g, 10 mmoles), K2CO3 (1.38 g, 10 mmoles) in DMF (15 ml) is introduced into a tube to be placed in a microwave oven and irradiated at 100° C. for 70 minutes, under magnetic stirring. The reaction mixture is then poured into water (200 ml) and extracted with AcOEt (2×75 ml). The organic phases are combined, washed with salt water, dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on a silica column (eluent: Heptane/AcOEt: 7/3). The expected compound is obtained in the form of a white solid with a yield of 25% (666 mg). Melting point: 177-178° C.
Reaction SMILES: C1(C[NH:8][CH2:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH2:13][CH2:12][NH:11]2)C=CC=CC=1.[ClH:22].O1CCOCC1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[Cl-:22].[Cl-:22].[NH3+:8][CH2:9][CH:10]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][CH2:12][NH2+:11]1
Reactant: [H][H]
Reactant: Cl
Reactant: c1ccc(CNCC2NCCCC2c2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: [Cl-]
Product: [NH3+]CC1[NH2+]CCCC1c1ccccc1
Reaction time: 18 h
Yield: 61 %

Procedure:
To a solution of 1-phenyl-N-[(3-phenylpiperidin-2-yl)methyl]methanamine (101 mg, 0.359 mmol) in methanol (5 ml) were added 4M HCl in dioxane (0.090 ml, 0.359 mmol) and palladium hydroxide (28.9 mg, 0.036 mmol). The reaction mixture was charged with 1 atm hydrogen gas and allowed to stir for 18 h. The reaction mixture was filtered through celite, and to the filtrate was added 4M HCl in dioxane (0.090 ml, 0.359 mmol). The reaction was allowed to stir for 1 h and concentrated in vacuo to yield 2-(ammoniomethyl)-3-phenylpiperidinium dichloride (61%). LCMS (M+H)=191.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:32]=O)=[C:26]3[C:31]=2[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:32]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[C:26]3[C:31]=2[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: O=Cc1[nH]c(C(=O)NCCCN2CCCC2)c2c1CCCC2
Product: O=C1Nc2ccc(Br)cc2C1=Cc1[nH]c(C(=O)NCCCN2CCCC2)c2c1CCCC2
Yield: 21.9 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (80 mg, 0.4 mmol) was condensed with 3-formyl-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid (3-pyrrolidin-1-ylpropyl)amide (120 mg) to give 43 mg (22%) of the title compound as a tan-orange solid.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:19][CH:18]=1)[N:12]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:11][CH2:10]2.CO>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17]1[CH:18]=[CH:19][C:20]([O:23][S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=1)[N:12]([C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:11][CH2:10]2
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C3c4ccc(O)cc4CCN3C(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 134.6 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (16.2 ml, 16.2 mmol) was added slowly to a solution of toluene-4-sulfonic acid 4-(6-methoxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl ester (7.459 g, 14.8 mmol) in anhydrous CH2Cl2 (500 ml) at 0° C. under N2. After stirring at 0° C. for 1 hr, the reaction mixture was warmed to rt and stirred at rt for 18 hr. MeOH (250 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to give 9.793 g of brown residue. Purification by flash chromatography, eluting with hexane:EtOAc (7:3) gave 2.764 g (38% yield) of white solid.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO.O1CCOCC1>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9][NH:8]3)=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1(C)CNC(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 119.2 %

Procedure:
To a clear brown solution of 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester (10.4 g, 22.7 mmol) in methanol (41 mL) was added HCl in dioxane (4M, 91 mL). The reaction was stirred for 30 minutes at room temperature, during which time a pale brown precipitate began to form. The mixture was poured into a 250-mL volume of vigorously stirring Et2O. The resulting slurry was stirred at room temperature for 15 minutes, then filtered to yield a pale orange solid. The solid was placed on the high-vacuum pump overnight, after which 9.71 g of 6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-β-carbolin-8-yl)-amide was obtained (99% yield). 1H-NMR (DMSO-d6, 300 MHz) δ 13.47 (s, 1); 11.77 (s, 1); 9.42 (s, 1); 8.86 (d, 1); 8.66 (d, 1); 8.58 (d, 1); 8.25 (d, 1); 4.41-4.37 (m, 2); 4.05 (dd, 1); 3.32-3.28 (m, 1); 3.04-3.00 (m, 1); 1.34 (s, 3); 1.30 (s, 3). NH4OAc standard conditions. DAD Rf=1.48 min. M+H=359.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[C:29]([C:37]([F:39])([F:38])[F:40])[CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: O=C(Cl)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: N=C(N)NC(=O)c1cn(-c2cc(C(F)(F)F)nc3ccccc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 8.4 cm3 (4.2 mmol) of a 0.5N solution of sodium methoxide in methanol are added to 0.401 g (4.2 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and concentrated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.35 g (0.85 mmol) of 3-chlorocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm3 of dichloromethane, are then added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.1 g of 3-guanidinocarbonyl-1-(2-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 216° C. Mass spectrum (EI): m/e 397 (M+.), m/e 339 (base peak).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([OH:10])=[O:9].[C:12](O)([CH3:15])([CH3:14])[CH3:13].[I-].ClC1C=CC=C[N+]=1C.C(N(CCCC)CCCC)CCC>ClCCl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8]([O:10][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)(C)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Cl)nnc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.6 %

Procedure:
A mixture of 3,6-dichloropyridazine-4-carboxylic acid (5.79 g, 30 mmol), tert-butanol (2.45 g, 33 mmol), 2-chloro-1-methylpyridinium iodide (6.12 g, 24 mmol), and tributylamine (8.9 g, 48 mmol) in dichloromethane (52 mL) was stirred at refluxing under N2 for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified using a silica gel cartridge (330 g) which was pretreated with 1% Et3N in hexanes for 10 min at 10 mL/min, eluting with a gradient of EtOAc (0-50%) in hexanes to afford 6.1 g (81%) of the title compound as a white solid. HPLC/MS (Method B): retention time=2.95 min, [M+H]+=249.1.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]#N)=[CH:6][CH:5]=[N:4][NH:3]1.OS(O)(=O)=O.C([O-])([O-])=[O:16].[Na+].[Na+].[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:8]([C:7]1[C:2](=[O:1])[NH:3][N:4]=[CH:5][CH:6]=1)=[O:16])[CH3:22]
Reactant: CCO
Reactant: N#Cc1ccn[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccn[nH]c1=O
Temperature: 25 °C
Yield: 31 %

Procedure:
3-Oxo-2,3-dihydro-pyridazine-4-carbonitrile (1 g, 8.26 mmol) was heated in a mixture of ethanol (2 ml) and conc. H2SO4 (1.1 ml) to 100° C. (oil-bath temperature) overnight. The reaction mixture was then allowed to cool to ambient temperature, poured onto ice and carefully neutralized with solid Na2CO3. The mixture was extracted three times with CHCl3 and the combined extracts were dried (Na2SO4) and evaporated. The remaining residue was then purified by column chromatography (silica gel, heptane/ethyl acetate 70:30 to 35:65) to give the title compound (433 mg, 2.58 mmol; 31%) as white solid. MS: m/e=169.1 [M+H+].
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=2)=[CH:6][C:5]=1[OH:26].N12CCCN=[C:34]1[CH2:33][CH2:32][CH2:31]CC2.BrCC1CC1>C(O)C>[CH:33]1([CH2:34][O:26][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:25])[C:18]4[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=4)[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:27])[CH2:31][CH2:32]1
Reactant: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCC1CC1
Solvent: CCO
Product: Cc1cccnc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC3CC3)c2)n1

Procedure:
0.12 g of N-[2-(4-difluoromethoxy-3-hydroxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide obtained in Example 97 and 0.15 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene were dissolved in 4 ml of ethanol. 0.15 ml of (bromomethyl)cyclopropane was added thereto and refluxed with heating for 3 hours. The solvent was distilled off, and water was added to the residue. Ethyl acetate extraction was performed. The organic layer was washed twice with water, and concentrated. The residue was purified by silica gel column choromatography (n-hexane:ethyl acetate=1:1). The obtained crude crystals were recrystallized using an ethanol-n-hexane mixture, and 60 mg of white powdery N-[2-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-3-methylpicolinamide was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][NH:31][C:30]1=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:36]2[CH2:35][CH2:34][C:33]3([O:29][C:30](=[O:39])[NH:31][CH2:32]3)[CH2:38][CH2:37]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CNC(=O)O4)n(C)c2n1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and 1-oxa-3,8-diazaspiro[4.5]decan-2-one (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 95:5 to 90:10 to 85:15) to afford 327 as a white solid (77 mg, 56%). LCMS (Method G): RT=5.35 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.9 (m, 1 H); 7.72 (m, 1 H); 7.29 (m, 2 H); 4.99 (bs, 1 H); 4.35 (m, 4 H); 3.90-3.83 (m, 7 H); 3.80 (s, 2 H); 3.36 (s, 2 H); 2.95 (s, 3 H); 2.76-2.65 (m, 4 H); 2.03 (m, 2 H) and 1.82 (m, 2 H)
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC(NC(=O)CCCc2ccccc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (268 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (575 mg, 83%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCC1CCOCC1

Procedure:
Prepared similarly to Intermediate 220 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromopropyl)tetrahydro-2H-pyran.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1([CH3:24])[C:18]2[C:11]([CH:12]=[C:13]3[C:17]=2[CH:16]=[N:15][N:14]3[CH2:19][C@H:20](O)[CH3:21])=[C:10]([CH3:23])[CH:9]=[CH:8]1.C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@@H:20]([CH3:21])[CH2:19][N:14]1[C:13]2=[CH:12][C:11]3[C:18]([C:7]([CH3:24])([CH3:6])[CH:8]=[CH:9][C:10]=3[CH3:23])=[C:17]2[CH:16]=[N:15]1)=[N+:33]=[N-:34]
Reactant: CC1=C2C=c3c(cnn3C[C@@H](C)O)=C2C(C)(C)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C2C=c3c(cnn3C[C@H](C)N=[N+]=[N-])=C2C(C)(C)C=C1
Yield: 80.3 %

Procedure:
0.5 ml (6.24 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 0.8 g (3.1 mmol) of (R)-1-(4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]-pyrazol-1-yl)-propan-2-ol and 1.75 ml (12.5 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 150 ml of dichloromethane, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.41 g (6.3 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 0.7 g (80%) of (S)-1-(2-azido-propyl)-4,4,7-trimethyl-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a light yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([Cl:3])=[O:19])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2cc(C(=O)O)on2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)Cl)on2)cc1

Procedure:
Using 40 ml of thionyl chloride, 7.3 g (35.9 mmol) of 3-(4-methylphenyl)isoxazole-5-carboxylic acid obtained above in the procedure (2) were refluxed for 4 hours in the presence of 0.1 ml of dimethylformamide. Thionyl chloride was distilled off under reduced pressure, followed by the addition of 100 ml of benzene. The resultant mixture was distilled under reduced pressure so that 3-(4 -methylphenyl)isoxazole-5-carboxylic acid chloride was obtained as a solid. The solid was provided for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[O:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N)cc2o1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2o1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (102 mg, 0.688 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (151 mg, 65%), single spot at Rf 10.50 (60:40 hexane:ethyl acetate). mp 127.1-127.5° C., HPLC purity 97% (tR 2.05 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.85 (1H, dd, J=8.1, 1.1 Hz), 7.53 (1H, dd, J=8.1, 1.3 Hz), 7.45 (1H, d, J=8.4 Hz), 7.27 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=7.9 Hz), 6.93 (1H, s, N—H), 6.86 (1H, dd, J=8.4, 2.2 Hz), 2.71 (3H, s), 2.58 (3H, s). LCMS: 335.14 (M−). FAB-MS (MH+, C15H13ClN2O3S): calcd 337.0413, found 337.0406.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11]([CH3:13])([CH3:12])[C:10](=[O:14])[N:9]2[CH:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl>[CH3:12][C:11]1([CH3:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:3][CH:4]=2)[N:9]([CH:15]2[CH:16]3[CH2:24][CH:20]4[CH2:19][CH:18]([CH2:23][CH:22]2[CH2:21]4)[CH2:17]3)[C:10]1=[O:14]
Reactant: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1c1ccc(NS(C)(=O)=O)cc1
Reaction time: 3 h
Yield: 18.3 %

Procedure:
Under an argon atmosphere, a solution of 1-(4-aminophenyl)-4,4-dimethyl-2-(adamantan-2-yl)-1,2-diazetidin-3-one (30.0 mg, 0.0920 mmol) prepared in Example 183 in dichloromethane (1 mL) was added with triethylamine (18.6 mg, 0.184 mmol) and methanesulfonyl chloride (15.8 mg, 0.138 mmol) at room temperature, and the resultant was stirred at the same temperature for 3 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=1:1), and the title compound (6.80 mg, 18.3%) was obtained as a brown amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][O:32]CC)=[CH:4][CH:3]=1.C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[CH2:29][CH2:30][CH2:31][OH:32])=[CH:35][CH:36]=1
Reactant: CCOCCCc1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Cn1c(=O)n(CCCO)c(=O)c2c1nc(CCCO)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-8-(3-hydroxypropyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.061 mmol, example 48, step 3) in ethyl alcohol (20 mL) was added acetyl chloride (0.2 mL, 2.80 mmol). The reaction was stirred at 0° C. for 10 min. The mixture was concentrated to give a crude product, which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1,8-bis(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (15 mg, 60.6% yield) as a white solid. 1H-NMR (CD3OD) δ 7.37-7.35(d, 2H), 7.21-7.22(d, 2H), 5.62(s, 2H), 4.11-4.08(t, 2H), 3.62-3.59(t, 4H), 3.56(s, 3H), 2.87-2.83(t, 2H), 1.95-1.83(m, 4H). LCMS retention time 1.801 min; LCMS MH+ 407.