Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:40])[CH2:10][CH:11]([N:23]1[CH:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:24]1)[C:12]([NH:14][C@H:15]1[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]1=[O:22])=[O:13])C1C=CC=CC=1>CCO>[C:31]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([N:25]2[CH:26]=[CH:27][N:23]([CH:11]([C:12]([NH:14][C@H:15]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:16]3=[O:22])=[O:13])[CH2:10][C:9]([OH:40])=[O:8])[CH2:24]2)=[CH:33][CH:32]=1
Reactant: O=C(CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1)OCc1ccccc1
Solvent: CCO
Product: O=C(O)CC(C(=O)N[C@H]1CCCCNC1=O)N1C=CN(c2ccc(-c3ccccc3)cc2)C1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
According to the procedure described in Example 1(a), a suspension of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid benzyl ester in EtOH was hydrogenolyzed after 90 minutes to provide 779 mg (94%) of 3(RS)-(3-biphenyl-4-yl-1H-imidazol-1-yl)-N-(hexahydroazepin-2-on-3(S)-yl)succinamic acid as a solid.
Reaction SMILES: [C:1]1([C:9]([O:11]CC)=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.C(O)C>[OH-].[Na+]>[CH2:7]([O:6][C:4]([C:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CC1
Yield: 94 %

Procedure:
Diethyl 1,1-cyclopropane dicarboxylate (20 g) was hydrolyzed in 1N NaOH (107 ml) and ethanol (220 ml) for 16 hours, and the ethanol was removed by distillation under reduced pressure. The remaining starting material was removed by using ethyl acetate and the aqueous layer was acidified by 1N HCl. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified by silica gel column to give the title compound in a yield of 94%.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[CH:1]1([N:7]2[C:14](=[O:15])[CH2:13][CH:9]([C:10]([OH:12])=[O:11])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(C2CCCCC2)C1
Temperature: 110 °C
Yield: 58.1 %

Procedure:
A mixture of cyclohexanamine (3.70 mL; 31.94 mmol) and 2-methylenesuccinic acid (5.04 g; 41.62 mmol) in water (10 ml) was heated in a sealed tube at 110° C. for 21 hours. After cooling to room temperature, 6N NaOH (10 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 3.92 g (58%) of 1-cyclohexyl-5-oxopyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [K+].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH-:12])(=[O:11])=[O:10])=[N:7][CH:8]=1.[Cl:13][C:14]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CS(C)=O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:18]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([Cl:13])[N:15]=[C:16]([CH3:30])[N:17]=2)(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Reactant: Cc1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
At room temperature 2.95 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) was added to a suspension of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine (Example 7b) in 30 ml DMSO. The mixture was stirred at room temperature for 48 h and was then poured onto 300 ml of water. The aqueous solution was extracted twice with 200 ml of diethyl ether. The organic layers were extracted with water and the aqueous layers were combined and acidified with 3 ml of acetic acid to pH 4. Precipitation of the product was enhanced by adding 100 ml of saturated aqueous sodium chloride and cooling the mixture to 0° C. Eventually, the precipitate was filtered off, washed with cold water and dried under high vacuum to give 2.26 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR=4.79 min, [M+1]+=421.42, [M−1]−=419.46.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][N:9]2[S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:23][OH:24]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][CH3:23])[CH2:10][NH:9][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC2c2ccc(Cl)cc2)cc1
Reactant: CO
Solvent: ClCCl
Product: COC(CNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 76.5 %

Procedure:
2-(4-Chlorophenyl)-1-(4-nitrophenylsulfonyl)aziridine (0.276 g, 0.815 mmol) was dissolved in 8 ml of methanol and 4 ml of dichloromethane. The reaction was stirred at ambient temperature for 5 days, and then concentrated. The crude material was on a Biotage SP1 system eluting with a 5-50% linear gradient of EtOAc in hexanes to yield 231 mg of the title compound (76.5% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)=[CH:4][CH:3]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To the suspension of 4-(4-bromo-phenyl)-1H-indole (1.20 g, 4.41 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (54 mL) was added pyridinium tribromide (4.23 g, 13.23 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (30 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was suspended in water (300 mL) for 0.5 hour. The solid product was precipitated out, filtered, and washed repeatedly with water to remove the zinc salt and pyridine salt. After high vacuum dry, a pure product (1.12 g, 88%) was obtained.
Reaction SMILES: [CH3:1]SC.B.[NH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]2[O:25][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[N:22]=4)[N:17]=[CH:16][C:15]=3[NH:14][C:13]2=O)[CH2:8][CH2:7]1>O1CCCC1>[CH3:27][O:26][C:21]1[N:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]1[N:14]([CH3:1])[CH2:13][CH:12]([C@H:9]3[CH2:8][CH2:7][C@H:6]([NH2:5])[CH2:11][CH2:10]3)[O:25][C:24]2=1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Reactant: CSC
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)CN3C
Temperature: 0 °C

Procedure:
Borane dimethyl sulfide complex (2M solution in tetrahydrofuran, 60.0 mL, 120.0 mmol, 24.5 eq) is added at room temperature to a stirred solution of 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one (1.67 g, 4.88 mmol, 1.0 eq) in tetrahydrofuran (600 mL). The reaction mixture is heated to reflux for 3 hours, cooled down to 0° C. and cautiously quenched with methanol (100 mL) and then evaporated to give crude trans-4-(6-methoxy-1-methyl-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexylamine that is directly engaged in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[N:9]/[S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:16](Br)[CH:17]=[CH2:18].[In]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH2:18][CH:17]=[CH2:16])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CC(C)(C)[S@@](=O)/N=C/c1cccc(Br)c1
Agent: [In]
Solvent: C1CCOC1
Product: C=CC[C@H](N[S@](=O)C(C)(C)C)c1cccc(Br)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 112.5 %

Procedure:
To round bottomed flask equipped with a reflux condensor was charged 161A (2.4673 g, 8.56 mmol), allyl bromide (0.889 mL, 10.27 mmol) and THF (40 mL) to which was added indium (1.180 g, 10.27 mmol) and the mixture heated to 60° C. under nitrogen where it was stirred for overnight. The reaction mixture was quenched by addition of water (40 mL) and the mixture stirred for 15 min, diluted with EtOAc (30 mL), and the phases separated. The aqueous phase was extracted with EtOAc (2×) and the combined organics washed with brine, dried (Na2SO4), filtered and evaporated to give a faint yellow colored oil which was placed under vacuum for overnight to give 161B (3.18 g, 89%). 1H NMR (500 MHz, CDCl3) δ 7.50 (t, J=1.8 Hz, 1H), 7.45-7.42 (m, 1H), 7.27-7.21 (m, 2H), 5.79-5.69 (m, 1H), 5.24-5.22 (m, 1H), 5.22-5.19 (m, 1H), 4.48 (ddd, J=8.1, 5.5, 2.1 Hz, 1H), 3.69 (s, 1H), 2.64-2.58 (m, 1H), 2.47 (dt, J=14.0, 8.4 Hz, 1H), 1.23 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:35])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:43][S:44]([CH2:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:35])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:53]3[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][S:44]([CH3:43])(=[O:45])=[O:46])[CH2:51][CH2:52]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:25]=3[O:32][CH2:33][CH3:34])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (˜175 mg, 0.26 mmol) in dichloromethane (10 mL) and triethylamine (0.35 g, 3.34 mmol) at 0° C. was treated with 1-(3-methanesulfonylpropyl)piperazine (0.11 g, 0.39 mmol, prepared as described in Fotouhi, N. et a. WO 2005110996) for 0.5 h. The reaction was washed with cold water, dried over anhydrous magnesium sulfate, filtered and evaporated to give a solid. Trituration with ether and filtration gave the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C35H40N5O4SCl2 [(M+H)+] 696.2173, observed 696.2167.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].CC1C=CC(S(O[CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])(=O)=O)=CC=1>CS(C)=O>[OH:1][C:2]1[C:9]([O:10][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cccc(O)c1O
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCCOCCOc1cccc(C#N)c1O
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of 2,3-dihydroxybenzonitrile (13.5 g, 1 eq.) in DMSO (200 mL) was added NaH (60%, 8 g, 2eq.) and the resulting solution was stirred for 1 h at 60° C. 2-(2-Methoxyethoxy)ethyl 4-methylbenzenesulfonate (20 g, 0.7eq.) in DMSO (100 mL) was added dropwise at 60° C. and stirring was continued for another 1 h. The reaction was quenched by NH4Cl (sat.), the mixture was extracted with EtOAc (300 mL×3) and the combined organic layers were dried over Na2SO4. The solvent was evaporated and the residue was purified by silicon column (EtOAc/PE=1/1) to give the title compound (6 g, 25%).
Reaction SMILES: C([O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)C.Br.[OH-].[Na+].Cl>O.O1CCOCC1.ClCCl.CO>[OH:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[N:15]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: OCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 18 h

Procedure:
Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.10 g, 9.4 mmol) and 48% hydrobromic acid (25 mL). Heat to reflux. After 18 hours, dilute with water and adjust the pH to 12 using aqueous 5 M sodium hydroxide solution. Extract three times with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Combine the residue and methanol (50 mL). Add a solution of hydrochloric acid (5.0 mL, 4 M, 20 mmol) in dioxane. Evaporate in vacuo to give a residue. Combine the give residue and dichloromethane. Extract with a saturated aqueous solution of sodium bicarbonate. Dry the organic layers over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].S(=O)(=O)(O)O>[CH2:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:12]1[O:14][CH2:13]1
Reactant: CCCCCCCCO
Reactant: ClCC1CO1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Product: CCCCCCCCOCC1CO1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
Octanol (195 g, 1.5 mole), 1.02 g (0.005 mole) of aluminum triisopropoxide and 0.7 g (0.007 mole) of 98% sulfuric acid were heated to 90° C. while stirring under a nitrogen gas atmosphere. To the reaction mixture, 92.5 g (1.0 mole) of epichlorohydrin was then added dropwise over 1 hour, followed by stirring for 4 hours. It was found that the conversion ratio of the raw material epichlorohydrin was 100%, while the yield of the resulting halohydrin ether was 95%. To the reaction mixture, 300 mL of a 4N aqueous solution of sodium hydroxide was added and the resulting mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the water layer was removed and the residue was purified by distillation under reduced pressure, whereby 175 g of octyl glycidyl ether (1,2-epoxy-4-oxadodecane) was obtained (total yield: 95%.).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[N:33][CH:34]=2)[CH:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:36][O:35][C:32]1[N:33]=[CH:34][C:29]([C:25]2[CH:24]=[C:23]([NH:20][C:21]3[O:13][C@:5]4([CH2:4][N:3]=3)[CH:10]3[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]3)[CH2:6]4)[N:28]=[CH:27][N:26]=2)=[CH:30][N:31]=1
Reactant: COc1ncc(-c2cc(N=C=S)ncn2)cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC3=NC[C@@]4(CN5CCC4CC5)O3)ncn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.093 g, 0.41 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.33 g, 1 mmol)) and 6-isothiocyanato-2′-methoxy-4,5′-bipyrimidine (0.1 g, 0.41 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.19 mL, 1.2 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-25% [9:1 methanol:ammonium hydroxide]-ethyl acetate) to afford (R)—N-(2′-methoxy-4,5′-bipyrimidin-6-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.072 g, 0.188 mmol, 46% yield) as an off-white solid. 1H NMR (400 MHz, MeOD) δ ppm 9.19 (2H, s), 8.80 (1H, d), 7.24 (1H, br. s.), 4.00-4.09 (4H, m), 3.76 (1H, d), 3.23 (1H, s), 3.08-3.15 (1H, m), 2.72-3.04 (4H, m), 1.97-2.22 (2H, m), 1.38-1.85 (3H, m). R.T.=1.22; [M+H]+=368.22.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]1[C:16]([CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:15][N:14]=[C:13]([C:21]3[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:23][C:24]4[O:28][C:27]([C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=4[CH:40]=3)[CH:12]=1)[NH:6]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:11]4[CH:12]=[C:13]([C:21]5[C:22]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:43])=[O:44])=[CH:23][C:24]6[O:28][C:27]([C:29]7[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=7)=[C:26]([C:36]([NH:38][CH3:39])=[O:37])[C:25]=6[CH:40]=5)[N:14]=[CH:15][C:16]=4[CH2:17][C:18]([CH3:20])([CH3:19])[N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc(-c4cc5c(F)cccc5[nH]4)c(C=C(C)C)cn3)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cc4c(cn3)CC(C)(C)n3c-4cc4c(F)cccc43)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A mixture of 5-(4-(4-fluoro-1H-indol-2-yl)-5-(2-methylprop-1-en-1-yl)pyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (100 mg, 0.156 mmol) and K3PO4 (166 mg, 0.781 mmol) in DMAc (0.8 mL) was stirred at 100° C. overnight. The mixture was then diluted with water (40 mL) and extracted with EA (20 mL*3). The organic layer was washed with brine (30 mL*3), dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (DCM:EA=1:1) to afford the product of 5-(11-fluoro-6,6-dimethyl-5,6-dihydroindolo[2,1-a][2,6]naphthyridin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 40.0%). 1H-NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.86˜8.00 (m, 4H), 7.61 (s, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.00˜7.18 (m, 4H), 6.72 (t, J=8.4 Hz, 1H), 6.01 (br s, 1H), 3.16 (s, 3H), 3.08 (br s, 2H), 2.93 (d, J=4.4 Hz, 3H), 2.77 (s, 3H), 1.69 (br s, 6H). MS (M+H)+: 641.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[NH:9][C:10](=[O:14])[C:11]([OH:13])=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CS(C)=O>[CH2:22]([O:12][C:11](=[O:13])[C:10]([NH:9][C:3]1[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:14])[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)C(=O)Nc1cccccc1=O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCOC(=O)C(=O)Nc1cccccc1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
A solution of [(2-oxo-3,5,7-cycloheptatrien-1-yl)amino]oxo-acetic acid (1.54 g, described in Example 30) and potassium carbonate (0.82 g) in dimethylsulfoxide (8 ml) is stirred at room temperature for 15 minutes. A solution of 5-bromopentane (1.52 ml) in dimethylsulfoxide (8 ml) is added and the resulting mixture is stirred at 80° C. for 40 minutes. The mixture is cooled to room temperature and poured over ice. The mixture is stirred for ten minutes and the precipitate is collected by filtration. The precipitate is dissolved in ether, treated with charcoal and crystallized by the addition of hexane to give the title compound, mp 87°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[N:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]=O.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[N:11][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ncoc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.40 g (8.00 mmol) of 4-chlorobenzoyl chloride, 1.00 g (10.09 mmol) of methyl isocyanatoacetate and 5.9 ml (42.39 mmol) of triethylamine are dissolved in 15 ml of dry THF and stirred at RT for 48 h. The solvent is then removed on a rotary evaporator. The residue is taken up in 20 ml of ethyl acetate and washed once with 5 ml of water. The organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The residue is suspended in 10 ml of cyclohexane and filtered off. It is then recrystallized from about 10 ml of methanol. This gives needle-shaped crystals which are dried in a drying cabinet at 50° C. A further product fraction is obtained by reprecipitation after recrystallization.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29](O)=[O:30]>>[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29]([NH:1][N:2]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19])=[O:30]
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Product: Cc1ccc(-c2nn(NC(=O)C[C@@H]3CC[C@H]4C[C@@H]3C4(C)C)c(=O)c3ccccc23)cc1

Procedure:
The product of Example 135A and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.34 (s, 1H), 8.37-8.41 (m, 1H), 7.86-8.04 (m, 2H), 7.72-7.77 (m, 1H), 7.46-7.50 (m, 2H), 7.36-7.40 (m, 2H), 2.51-2.60 (m, 2H), 2.42 (s, 3H), 2.29-2.45 (m, 2H), 1.79-2.06 (m, 5H), 1.47-1.63 (m, 1H), 1.20 (s, 3H), 1.07 (d, J=0.6 Hz, 3H), 0.91 (d, J=9.5 Hz, 1H); MS (APCI+) M/Z 416 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:12].[O-]CC.[Na+]>C(O)C>[C:13]12([C:11](=[O:12])[CH:10]=[CH:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-fluorobenzaldehyde (6.01 ml, 56.10 mmol, Aldrich) and 1-adamantyl methyl ketone (10.00 g, 56.10 mmol) in absolute ethanol (100 ml) was treated with a solution of sodium ethoxide in ethanol (21% by weight solution; 2.08 ml, 5.61 mmol). A precipitate soon fell out of solution. After stirring at room temperature for 48 hours, the mixture was cooled to -10° C. and the precipitate was collected by filtration. The solid was washed with cold ethanol, dried in vacuo and recrystallized from hexane. The title compound was obtained as an off-white solid (9.20 g, 57.8%).