Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:50]2[CH:55]=[C:54]([O:56][CH3:57])[C:53]([O:58][CH3:59])=[C:52]([O:60][CH3:61])[CH:51]=2)=[C:8]([CH:49]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:48])[C:27]3[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:28]=3[C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[CH2:22][CH2:21]2)[CH2:13][CH2:12]1)=[O:10])([O-])=O>[Pd].C(O)(=O)C.CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:28]([C:36]2[CH:37]=[C:38]([O:46][CH3:47])[C:39]([O:44][CH3:45])=[C:40]([O:42][CH3:43])[CH:41]=2)=[C:27]([CH:32]=1)[C:26]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]3[CH:49]=[C:4]([NH2:1])[CH:5]=[CH:6][C:7]=3[C:50]3[CH:51]=[C:52]([O:60][CH3:61])[C:53]([O:58][CH3:59])=[C:54]([O:56][CH3:57])[CH:55]=3)[CH2:12][CH2:13]2)[CH2:21][CH2:22]1)=[O:48]
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc([N+](=O)[O-])ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-c2ccc(N)cc2C(=O)N2CCN(CCCN3CCN(C(=O)c4cc(N)ccc4-c4cc(OC)c(OC)c(OC)c4)CC3)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
10% Palladium on carbon (50 mg) was added to a solution in acetic acid-methanol (1 ml-i ml) of 1,3-bis[4-[5-nitro-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]-propane dthydrochloride (91 mg; 0.10 mmol) synthesized by the process described in Example 8. After the mixture was stirred at room temperature for 3 hours under hydrogen, the catalyst was removed from the reaction mixture by filtration. The filtrate was concentrated under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the resultant concentrated residue to conduct extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 37%) of 1,3-bis[4-[5-amino-2-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]propane as a colorless oil.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C(OC([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([C:33]([OH:35])=O)[N:30]([CH3:32])[CH:31]=2)=[CH:23][CH:22]=1)=O)(C)(C)C.[NH2:36][C:37]1[CH:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:28]=[C:29]([C:33]([NH:36][C:37]3[CH:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=3)=[O:35])[N:30]([CH3:32])[CH:31]=2)=[CH:25][CH:26]=1
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Reactant: COC(=O)c1cc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
Two eq of EDCl and 2.5 eq of DMAP were added to a stirred solution of 6 (0.45 gm, 1.2 eq) in DMF (8 mL) and the mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-pyrrole-2-carboxylate (0.18 g, 1.18 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed with citric acid (100 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 9a (0.58 gm, yield 90.6%) was used for the boc deprotection step to afford 9 without further purification. For boc deprotection, 0.29 gm of 9a was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (9). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 9. Yield 0.21 gm, 95%.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>C(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[N:18]=2)(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(F)n2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(F)n2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-fluoropyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (48 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 22 mg, 53%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH2:19]([NH2:22])[CH2:20][OH:21].CCN(C(C)C)C(C)C>CCCCO>[N+:16]([C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:22][CH2:19][CH2:20][OH:21])[CH:4]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 57 %

Procedure:
73 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 23 mg 2-ethanolamine and 81 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH=10:1. 2-(6-(3-Nitrophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:28][CH2:27][C:13]2([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[NH:16][C:15](=[O:26])[CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:29]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:28][CH2:27][C:13]2([N:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:16]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[C:15](=[O:26])[CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)COc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NN2Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(CN2C(=O)CC3(CCN(C(=O)OC(C)(C)C)CC3)N2Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
NaH (24 mg, 0.50 mmol) was added slowly to a solution of 84AF84-19 (0.149 g, 0.41 mmol) in dry DMF (5 mL) and the mixture stirred at rt for 30 min. A solution of 4-isobutoxybenzyl bromide 69NLS69 (117 mg, 0.48 mmol) in dry DMF (1 mL) was added dropwise to the mixture. After 1 h stirring at rt the mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with a stepwise gradient of 3-6% methanol in dichloromethane, followed by preparative reversed phase HPLC (C18) afforded the desired compound (109 mg, 50%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([N+:39]([O-:41])=[O:40])[C:33]=1[O:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC12CC3(C)OC(C)(CC(C)(O3)O1)P2C1C=CC=CC=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:36][C:35]1[CH:37]=[CH:38][C:32]([C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)(=[O:21])=[O:22])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)=[C:33]([O:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[C:34]=1[N+:39]([O-:41])=[O:40]
Reactant: Nc1ccc(Br)c(Oc2ccc(F)cc2F)c1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Agent: [Pd]
Agent: CC12CC3(C)OC(C)(CC(C)(O1)P3c1ccccc1)O2
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc(N)c([N+](=O)[O-])c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 47.7 %

Procedure:
A suspension of 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.17 g, 0.40 mmol), 4-bromo-3-(2,4-difluorophenoxy)-2-nitroaniline (0.14 g, 0.40 mmol), potassium phosphate (0.22 g, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.01 g, 0.01 mmol), and 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.13,7]decane (0.0139 g, 0.0475 mmol) in 1,4-dioxane (4 mL) and water (0.9 mL) was degassed with nitrogen for 5 min and stirred at 80° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 40% EtOAc/hexanes) gave the desired product (108 mg, 23%) as a brown oil. LCMS calculated for C27H21F2N4O6S (M+H)+: m/z=567.1. found: 567.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1)[CH3:9]
Reactant: CC(OC[C@H]1CO1)c1ccccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(OC[C@H]1CO1)c1ccccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
(R)-2-[1-(2-Bromophenyl)ethoxymethyl]oxirane (8.24 g) was dissolved in toluene (38 ml) and ethanol (150 ml), 2M-aqueous sodium carbonate (80 ml), 4-cyanophenylboronic acid (5.65 g) and tetrakis(triphenylphosphine)palladium(0) (1.85 g) were successively added, and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted 3 times with diethyl ether. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the title compound (2.40 g).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]O)[C:5]=12.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:6]1[C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccn2ccnc12
Product: ClCc1cccn2ccnc12
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of imidazo[1,2-a]pyridin-8-ylmethanol (800 mg) and excess thionyl chloride was stirred at 70-80° C. for 8 h. Excess thionyl chloride was removed under vacuum. The residue was then diluted with toluene and evaporated. This procedure was repeated 3 times.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetic acid (321 mg, yield 66%) as colorless crystals. m.p. 156-157° C. (decomposition)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[C:15]([O:17][CH3:18])[C:12]([C:13]#[N:14])=[C:11]([F:19])[CH:10]=1.[N:20]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>C(#N)C>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:20][C:21]([N:6]2[CH2:7][C@H:2]([CH3:1])[N:3]([C:9]3[CH:16]=[C:15]([O:17][CH3:18])[C:12]([C:13]#[N:14])=[C:11]([F:19])[CH:10]=3)[CH2:4][C@H:5]2[CH3:8])=[O:22])=[CH:24][CH:25]=1)#[N:28]
Reactant: COc1cc(N2C[C@@H](C)NC[C@@H]2C)cc(F)c1C#N
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: CC#N
Product: COc1cc(N2C[C@@H](C)N(C(=O)Nc3ccc(C#N)cc3)C[C@@H]2C)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
Into 20 ml of acetonitrile was dissolved 500 mg of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-fluoro-6-methoxybenzonitrile, and then 274 mg of 4-isocyanatobenzonitrile was added thereto, followed by 1 hour of stirring at room temperature. The reaction solution was concentrated, followed by addition of ethyl acetate and filtration. The filtrate was removed by evaporation and the resulting powder was crystallized from hexane-ethyl acetate (85:15, v/v) to obtain 535 mg of the title compound.
Reaction SMILES: Cl.[N:2]1([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1([C:27]2C=CC(CC(O)=O)=C[CH:28]=2)C=NN=N1.C12N(C(OC(C)(C)C)=O)C(CC1)CNC2>>[CH:4]12[NH:5][CH:6]([CH2:27][CH2:28]1)[CH2:7][N:2]([C:8](=[O:21])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:14][CH:15]=1)[CH2:3]2
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: Cl
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from [4-(1H-tetrazol-1-yl)phenyl]acetic acid and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC/MS: [(M+1)]+=299.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of benzo[d][1,3]dioxol-5-ol (5.000 g; 36.20 mmol), and K2CO3 (5.503 g; 39.80 mmol) in anh. acetone (100 ml) was stirred at rt, under nitrogen, for 1 h. Iodomethane (28.258 g; 199.00 mmol) was then added, and the resulting mixture was heated at reflux, under nitrogen, for 20 h. After cooling to rt, the reaction mixture was filtered over a pad of celite, and the filtrate was concentrated to dryness under reduced pressure. Et2O and water were added, and the organic layer was further washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 5-methoxybenzo[d][1,3]dioxole as a yellow oil. LC-MS (conditions A): tR=0.66 min.; no ionisation.
Reaction SMILES: CC1(C)N([O])C(C)(C)CCC1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH2:24][OH:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([CH:24]=[O:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)C1
Agent: CC1(C)CCCC(C)(C)N1[O]
Product: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1

Procedure:
The alcohol starting materials can be prepared by the 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO) mediated oxidation of (S)-3-hydroxymethylpyrrolidine-1-carboxylic acid t-butyl ester to yield (S)-3-formylpyrrolidine-1-carboxylic acid t-butyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.CN(C)CCN(C)C.C[Mg+].[Br-].[Li]CCCC.CN([CH:39]=[O:40])C.[Cl-].[NH4+]>C1COCC1.CCCCCC.CCOCC>[CH:39]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1)=[O:40]
Reactant: CN(C)C=O
Reactant: CN(CC(O)c1ccc(Br)cc1)C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(CC(O)c1ccc(C=O)cc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
tert-Butyl 2-(4-bromophenyl)-2-hydroxyethyl(methyl)carbamate (36.7 g, 111.2 mmol) was dissolved in dry THF (600 ml) under N2 and tetramethyl ethylenediamine (42.2 ml, 32.5 g, 280.1 mmol) was added. The stirred mixture was cooled in an ice bath and a 3M ether solution of MeMgBr (46.4 ml, 139.3 mmol). After stirring for 1 hr a 1.6M hexane solution of nBuLi (150 ml, 240 mmol) was added and stirred for an additional 1 hr at which time dry DMF (50 ml, 47.2 g, 647 mmol) was added. After 1 hr a satd. solution (100 ml) of ammonium chloride was added. Most of the organic solvent was evaporated and the residual mass was extracted with ethyl acetate (3×500 ml), washed with water (300 ml) and brine (100 ml) then dried over magnesium sulfate. Filtration and evaporation gave a viscous oil that was chromatographed over silica gel (500 g). Elution with 25-40% ethyl acetate-hexane gave the product as a pale yellow gum (21.3 g) which very slowly crystallized to a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[C:14]4[C:18]([CH:19]=[CH:20][C:12]=3[O:11][CH2:10]2)=[N:17][O:16][N:15]=4)[C:2]1=[O:21].[H-].[Na+].[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[CH2:24]([O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:13]4[C:14]5=[N:15][O:16][N:17]=[C:18]5[CH:19]=[CH:20][C:12]=4[O:11][CH2:10]3)[C:2]2=[O:21])=[N:36][CH:37]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1N(Cc2ccc(OCc3ccccc3)cn2)c2ccccc2C12COc1ccc3nonc3c12
Reaction time: 0.33 h
Yield: 5.1 %

Procedure:
To a solution of 7H-spiro[benzofuro[4,5-c][1,2,5]oxadiazole-8,3′-indolin]-2′-one (0.400 g, 1.4 mmol) in anhydrous N,N-dimethylformamide (7 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.086 g, 3.6 mmol) at 0° C. and the mixture was stirred for 20 minutes. 5-(Benzyloxy)-2-(chloromethyl)pyridine (0.44 g, 1.9 mmol) was added and the reaction mixture was stirred at ambient temperature for 19 h. Potassium iodide (˜10 mg, catalytic amount) was added and the reaction mixture was stirred at 60° C. for 2 h, at ambient temperature for 43 h, at 60° C. for 7 h and at ambient temperature for 3 days. Saturated aqueous ammonium chloride (7 mL) and water (30 mL) were added and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (2×20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (3/2), followed by trituration in hexanes to afford 1′-{[5-(benzyloxy)pyridin-2-yl]methyl}spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one (0.034 g, 5%) as a pale yellow solid: mp 209-212° C.; 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=2.7 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.45-7.23 (m, 8H), 7.18 (d, J=7.5 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 6.92 (J=7.8 Hz, 1H), 5.39 (d, J=15.9 Hz, 1H), 5.27 (d, J=9.6 Hz, 1H), 5.11 (s, 2H), 4.99 (d, J=9.3 Hz, 1H), 4.87 (d, J=15.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.0, 163.0, 154.4, 148.3, 147.1, 144.9, 142.2, 137.8, 136.0, 129.8, 129.7, 128.7, 128.3, 127.6, 123.7, 123.6, 122.4, 122.3, 121.9, 119.3, 110.2, 107.0, 82.0, 70.4, 57.4, 46.0; MS (ES+) m/z 477.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH2:15][CH3:16])[C:5]1=[O:6])[CH2:2][CH3:3].[OH:17][C:18]1[N:23]=[N:22][C:21]([C:24](O)=O)=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.O>CO>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24]([C:21]3[N:22]=[N:23][C:18]([OH:17])=[CH:19][CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:6])[CH2:15][CH3:16]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)c1ccc(O)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2[nH]c(-c3ccc(O)nn3)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
To a solution of 1,3-dipropyl-5,6-diaminouracil (2.2 mmol) in methanol was added an equimolar amount of 6-hydroxy-pyridazine-3-carboxylic acid, followed by a slight excess of DCl ((N-(3-(dimethylamino)propyl)-N′ethylcarbodiimide hydrochloride). The mixture was stirred at room temperature for 4–5 hours until complete by TLC. Water was then added and the precipitate removed by filtration. The solid was dissolved in 10% aqueous NaOH (20 mL), then heated at 70° C. for 30 minutes. After cooling to room temperature, the reaction mixture was acidified to pH=5 with 10% hydrochloric acid and the precipitated product collected by filtration.