Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].[CH:20]1([CH2:25]Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[CH:20]1([CH2:25][N:4]2[C:5]3=[N:6][C:7]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([CH3:1])=[N:3]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCC1CCCC1
Reactant: Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(CC2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
To a solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine (6.0 g, 0.027 mol) in DMF (50 ml) at 0° C. was added 60% NaH/mineral oil dispersion (1.06 g, 0.027 mol) in one portion. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0° C. and cyclopentylmethyl bromide (4.3 g, 0.027 mol) was added dropwise over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 50 hours. The solvent was removed in vacuo, the yellow slurry was added to water (100 ml) and acidified with acetic acid. The resulting paste was stripped to dryness and the residue was slurried with ethanol. A tan solid was collected by filtration and purified by column chromatography on silica eluting with ether/ethanol/water (97.5/2/0.5) followed by recrystallization from cyclohexane to afford 2.2 g (26%) of 1-cyclopentylmethyl-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-amine, m.p. 177°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:23](O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([F:14])[C:7]2[N:13]=[CH:23][NH:10][C:8]=2[CH:9]=1)=[O:22]
Reactant: O=CO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 712.2 %

Procedure:
4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mmol) and 20% Pd(OH)2/C (9.00 g, 16.91 mmol) in ethanol (250 mL) are stirred at 40° C. for two hours under N2 and then at 95° C. for 16 hours. The reaction mixture is cooled to room temperature and filtered through Celite rinsing with ethyl acetate. The filtrate is concentrated under reduced pressure to give a yellow solid. The solid is triturated with diethyl ether to give 13.47 g (86%) of the desired product as a tan solid. MS APCI (+) m/z 286 (M+1) detected; MS APCI (−) m/z 284 (M−1) detected.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[C:34](Br)[C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:39](N(CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)C1CCCN(C(OC(C)C)=O)C2C=C(C)C(C)=CC1=2)(=O)C>>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([F:37])[C:34]([CH3:39])=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(Br)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(C)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-fluoro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7,8-dimethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 549 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:13]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)C1CC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(c2ccc(N)cc2)C1

Procedure:
A solution of this nitro compound (750mg.) in ethyl acetate (20ml.) was stirred for 16 hours with a 5% palladium on carbon catalyst (250mg.) in an atmosphere of hydrogen. The solution was filtered through a pad of "Hyflo" and evaporated to give methyl 3-(4-aminophenyl)cyclobutanecarboxylate. A solution of this amine (800mg.) in dry benzene (20ml.) was stirred under argon at room temperature during the dropwise addition of amyl nitrite (0.755ml.). The temperature of the reaction mixture was slowly (over 21/2 hours) raised to its boiling point and the mixture was then refluxed for 1 hour. The solvent was evaporated under reduced pressure and the residue was chromatographed on a dry column of silica gel `MFC` (supplied commercially by Hopkin and Williams) (25g.), eluting with toluene to give a mixture of cis and trans isomers of methyl 3-(4-biphenylyl)cyclobutanecarboxylate, RF = 0.70 (9:1 v/v toluene/ethyl acetate). The n.m.r. spectrum in deuteriochloroform showed the following characteristic features (δ values):
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][O:32][C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[C:39]=[O:40])=[CH:35][CH:34]=1>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:39]([NH:38][CH2:37][C:36]4[CH:41]=[CH:42][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[O:40])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: COc1ccc(CNC(=O)NC[C@H]2C[C@@H](n3cc(-c4cccc(OCc5ccccc5)c4)c4c(N)ncnc43)C2)cc1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(4-methoxy-benzyl)-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 4-methoxybenzyl isocyanate (Aldrich, Buchs, Switzerland). Analytical HPLC: tR=7.21 min (Grad 2); ES-MS: m/eo=562.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>CN(C)C=O.O>[CH:22]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][C:6]3[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:16][CH:15]=2)[CH:11]=[N:12]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: COc1ccc(Oc2ccc3[nH]ncc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc3c(cnn3C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-(4-methoxy-phenoxy)-1H-indazole (0.20 grams, 0.83 mmol) in 1 mL of dimethylformamide was added sodium hydride (0.040 grams of a 60% dispersion in mineral oil, 1.0 mmol). After shaking at room temperature for 10 minutes, the mixture was treated with 2-iodopropane (0.090 mL, 0.15 grams, 0.9 mmol). The mixture was heated to 50° C. for 6 hours. After cooling to room temperature, the mixture was diluted with water and was extracted 3 times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-30% ethyl acetate in hexanes, affording 1-isopropyl-5-(4-methoxy-phenoxy)-1H-indazole (90 miligrams) MS: 283.4 [M+H]+ and 2-isopropyl-5-(4-methoxy-phenoxy)-2H-indazole MS: 283.4 [M+H]+ (75 miligrams) as colorless syrup.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:13])[C:7](=[CH:11][CH:12]=1)[C:8]([OH:10])=[O:9])([O-:3])=[O:2].[C:14](Cl)(=[O:19])[CH2:15][C:16](Cl)=[O:17]>O1CCOCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:13][C:14](=[O:19])[CH2:15][C:16]([NH:13][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:17])[CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1COCCO1
Product: O=C(CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Nitroanthranilic acid (5.0 g, 26.6 mmol) was dissolved in dry dioxane (130 ml). To this solution, a solution of malonyl dichloride (1.45 g) in dry dioxane (5 ml) was added dropwise at room temperature. After stirring the mixture overnight, the precipitated crystals were collected by filtration, and washed with water and ether to give a pale yellow crystals of the title compound (2.58 g, 9.8%). m.p., 269°-270.5° C.
Reaction SMILES: [K].[C:2]([O:7][CH3:8])(=[O:6])/[CH:3]=[CH:4]/[CH3:5].[CH:9]([C:11]1[S:15][C:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:12]=1)=O.S([O-])(O)(=O)=O.[K+]>C(O)(C)(C)C.C(OCC)C.C(OCC)C.C(O)(C)(C)C>[C:19]([O:18][C:16]([C:14]1[S:15][C:11]([CH2:9][CH2:5][CH2:4][CH2:3][C:2]([O:7][CH3:8])=[O:6])=[CH:12][CH:13]=1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: C/C=C/C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [K]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCCCc1ccc(C(=O)OC(C)(C)C)s1
Temperature: 20 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
In an atmosphere of argon gas, potassium (25 g) was added to dried tert-butanol (820 ml) and refluxed for 3 hrs to give a solution. To the solution cooled to 20° C. was added diethyl ether (300 ml) and then slowly added a solution of methyl crotonate (63.93 g) and tert-butyl 5-formyl-2-thiophenecarboxylate (73.1 g) in tert-butanol/diethyl ether (2:1, 300 ml) keeping an inner temperature to 10° C. The mixture was stirred for 2 hrs at the same temperature and adjusted to pH 4 by adding 1N-potassium hydrogen sulfate aqueous solution (750 ml) under cooling. The mixture was extracted with diethyl ether, and the extract was washed with water and then saturated saline solution and distilled under reduced pressure to remove the solvent. The residue was dissolved in ethyl acetate (100 ml), to which 5% Pd-C (15 g:commercially available from Engelhard) was added. The mixture was vigorously stirred for 3 hrs at room temperature under hydrogen pressure of 4 kg/cm2. The reaction mixture was filtered to remove the catalyst and the filtrate was distilled under reduced pressure to remove the solvent. To the resulting residue were added dry methanol (200 ml), 4-(N,N-dimethylamino)pyridine (30 mg) and dichloromethane (250 ml), to which a solution of 1,3-dicyclohexylcarbodiimide (132 g) in dichloromethane (250 ml) was added slowly dropwise at 0° C. The mixture was stirred for 18 hrs at room temperature and cooled to 0° C. After adding acetic acid (30 ml), the mixture was stirred for 30 mins at 0° C. and for 30 mins at room temperature. The resulting precipitate was filtered off and the filtrate was concentrated to dryness under reduced pressure. Ethyl acetate (100 ml) was added to the residue and allowed to stand for 2 hrs at 0° C. Again, the resulting precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using diethyl ether-hexane=1:15→1:5, to obtain the captioned compound (61.4 g).
Reaction SMILES: [C:1]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:14]([O:13][C:1](=[O:12])[CH2:2][C:3]1[CH:11]=[CH:10][C:8]([O:9][CH2:17][CH2:18][CH2:19][Cl:20])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1ccc(OCCCCl)c(OC)c1
Yield: 65.1 %

Procedure:
A mixture of 50 g (0.238 mole of ethyl homovanillate (98% Aldrich), 75 g (0.476 mole) of 1-bromo-3-chloropropane and 98.7 g (0.71 mole) of anhydrous potassium carbonate in 1 L of acetone was heated at reflux for 24 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an oil which gradually crystallized to a semi-solid. The solid was recrystallized from ethyl ether-petroleum ether (30°-60°) to yield 44.4 g (65%) of title compound a white solid, mp 36°-38° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:24](=[O:26])[CH3:25])[C@H:10]([OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CO)[C@H](O)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of (±)-cis-3-hydroxy-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50.0 mmol, 11.6 g) in anhydrous DCM (500 mL) at room temperature was added triethylamine (100 mmol, 14.0 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added acetic anhydride (50.0 mmol, 4.72 mL) dropwise over 10 minutes. After completion of addition, the reaction was stirred for 12 hours while slowly coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with saturated NaHCO3 (2×50 mL), water (50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to provide (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (12.3 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1.[C-:13]#[N:14].[Na+]>C(O)C>[C:13]([CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)#[N:14]
Reactant: O=CN1CCC(CCCBr)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCCCC1CCN(C=O)CC1
Yield: 61.5 %

Procedure:
4-(3-Bromopropyl)-1-piperidinecarboxaldehyde (60 g, 0.256 M) and NaCN (25 g) in ethanol (600 ml) was refluxed for 7 hours, Solvent was removed, added water (300-400 ml) and extracted with CH2Cl2 (4×200 ml). The extracts, dried over Na2SO4 was stripped to dryness which was purified on silica gel columns, eluted with ethylacetate-hexane (8:2 parts by volume) to yield 4-(3-cyanopropyl)-1-piperidinecarboxaldehyde (28.4 g, 61% yield).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[CH:15]=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:32]([CH3:34])[CH3:33])[N:29]=[CH:30][N:31]=5)=[CH:22]4)[C:18]=3[CH:35]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[Li+].[OH-]>C1COCC1.O>[CH:32]([N:28]1[C:27]([C:21]2[N:20]=[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]4[CH:16]=[CH:15][C:14]([S:13][CH:10]5[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:36])=[O:2])[CH2:8][CH2:9]5)=[CH:35][C:18]=43)[CH:22]=2)=[N:31][CH:30]=[N:29]1)([CH3:34])[CH3:33]
Reactant: COC(=O)C(C)(C)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(=O)O)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (50 mg, 0.0979 mmol) in THF (4 mL) was added 1.0M LiOH in water (0.5 mL). The reaction mixture was first stirred at RT for 6 h, then left at RT for 7 days, and then heated at 120° C. for 1 h using microwave irradiation. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (C18, gradient 2-80% MeOH in H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (20 mg, 42%). LCMS: RT 2.45 min [M−H]+ 495.0.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][N:10]=1)CCC.[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32](I)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.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>[C:19]([N:27]1[C:35]2[CH:34]=[CH:33][C:32]([C:6]3[O:7][CH:8]=[CH:9][N:10]=3)=[C:31]3[CH2:37][C@@H:38]([N:40]([CH2:44][CH2:45][CH3:46])[CH2:41][CH2:42][CH3:43])[CH2:39][C@H:29]([C:30]=23)[CH2:28]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCN(CCC)[C@@H]1Cc2c(I)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)[C@@H]1Cc2c(-c3ncco3)ccc3c2[C@@H](C1)CN3C(=O)c1ccccc1
Yield: 67.5 %

Procedure:
A solution of 5.0 g (13.8 mmol) of the crude 2-tributylstannyloxazole prepared above and 6.8 g (13.9 mmol) of (+)(2aR,4S)-1-benzoyl-6-iodo-4-(di-n-propylamino)-1,2,2a, 3,4, 5-hexahydrobenz[cd]indole in 100 ml of toluene was treated with 0.7 g (0.6 mmol) of tetrakis(triphenylphosphine)palladium then refluxed under nitrogen for 20 hours. After cooling the reaction mixture was washed with a saturated brine solution and then dried over Na2SO4. Concentration in vacuo provided a viscous oil which was chromatographed over a silica gel column using a solvent gradient progressing from toluene to 1:1 toluene/EtOAc. The product from the column was dissolved in 1M HCl. This solution was then washed with ether, made alkaline with 5M NaOH, and extracted with CH2Cl2. Concentration of the extract in vacuo gave about 4 g of a brown oil. When this oil was dissolved in pentane a small amount of a red/brown resin separated leaving a clear, yellow solution. The resin was separated and the pentane was evaporated to provide a residue. This residue was crystallized by dissolving it in a small amount of CH2Cl2 and slowly adding isoctane. The crystalline (-)(2aR,4S)-1-benzoyl-6-(2-oxazolyl)-4-(di-n-propylamino)-1,2,2a,3,4, 5-hexahydrobenz[cd]indole, obtained in four crops, weighed 2.63 g. mp 103°-104° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1.CN(C)C(=O)C.[H-].[Na+].[ClH:29].[Cl:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>O>[ClH:30].[ClH:29].[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]1
Reactant: ClCc1ccccn1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Reaction time: 1 h

Procedure:
To a stirred mixture of 167 parts of ethyl 3-(1H-benzimidazol-2-ylamino)-1-pyrrolidinecarboxylate and 2790 parts of N,N-dimethylacetamide were added portionwise 61.0 parts of a sodium hydride dispersion 50% Upon completion, stirring was continued for 1 hour at 50° C. 127.2 Parts of 2-(chloromethyl)pyridine hydrochloride were added portionwise at 80° C. After complete addition, the whole was stirred for 2 hours at 80° C. After cooling, the reaction mixture was poured into 1000 parts of water. The product was extracted twice with methylbenzene. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 and 99:1 by volume) as eluents. The first and second fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol and 2,2'-oxybispropane. The salt was filtered off and dried, yielding 69.5 (24%) parts of ethyl 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidinecarboxylate dihydrochloride; mp. >140° C. (compound 23).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=S(=O)(c1cc2ccccc2o1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzofuran-2-sulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (0.4 mg). MS m/z 369 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([O:12][CH2:13][C:14]([O:16]C)=O)[C:9](=[O:11])[CH3:10].Cl>C(O)(C)(C)C.CCOCC>[CH3:7][CH:8]1[C:9](=[O:11])[CH2:10][C:14](=[O:16])[CH2:13][O:12]1
Reactant: COC(=O)COC(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC1OCC(=O)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mechanically stirred solution of potassium tert-butoxide in tert-butanol (1 M, 203 mL) under a nitrogen atmosphere was treated with anhydrous ether (125 mL), cooled to 0° C., treated with the product from Example 84B (15.5 g, 97 mmol) in ether (55 mL) over 2 minutes, stirred for 10 minutes and then treated with 2M HCl (240 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×, 200 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel eluting with ethyl acetate:formic acid:water:hexane (200:1:1:200) to provide the title compound.