Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[S:17][C:18]3[C:19]([N:28]=2)=[C:20]2[C:24](=[CH:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH2:21]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.Cl>N1CCCCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:21]1\[C:22](=[O:27])[NH:23][C:24]2[CH:25]=[CH:26][C:18]3[S:17][C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[N:28][C:19]=3[C:20]\1=2
Reactant: COc1cc[nH]c1C=O
Reactant: O=C1Cc2c(ccc3sc(-c4ccccc4)nc23)N1
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3sc(-c4ccccc4)nc3c21
Temperature: 90 °C
Reaction time: 1 h

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (11 mg, 0.088 mmol)(Bellamy, supra), piperidine (3 drops)(Aldrich), and 2-phenyl-6,8-dihydro-thiazolo[4,5-e]indol-7-one (21.4 mg, 0.08 mmol) (Example 3) were dissolved in DMF (3 mL). The mixture was heated to 90° C. and stirred at that temperature for 1 h. The mixture was cooled, poured into water, and acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the crude product was purified by reverse phase HPLC using acetonitrile-water as solvent, then crystallization from ethanol. (Yield 4.5 mg, 15%).
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6].Cl.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: CNCCC(O)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CNCCC(Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a cooled suspension of 20 g of γ-hydroxy-N-methylphenylpropylamine.HCl in chloroform are added dropwise 30 ml of thionylchloride. The mixture is subsequently stirred at room temperature till all solid substance has been dissolved. The solvent chloroform and the excess of thionylchloride are distilled off after which the residue is washed with ether and then made alkaline (pH=8) with a sodiumcarbonate solution (10%). The alkaline solution is subsequently extracted with ether and the ether extracts washed with water, dried and evaporated to dryness. The residue (oil) is used without any additional purification (yield 15.6 g; 85%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH2:14][C:13](=[CH2:15])[C@@H:12]1[CH2:11][N:10]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:35].[Na+].OO>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:14][C@H:13]([CH2:15][OH:35])[C@@H:12]1[CH2:11][N:10]([C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[CH2:9]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@]2(C(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@]12C[C@H](CO)[C@@H]1CN(C(=O)OCc1ccccc1)C2
Reaction time: 2 h

Procedure:
(1S,5S)-3-Benzyloxycarbonyl-6-methylene-3-azabicyclo[3.2.0]heptane-1-carboxylic acid tert-butyl ester (2.00 g, 5.82 mmol) was dissolved in tetrahydrofuran (40 mL). A 9-borabicyclo[3.3.1]nonane dimmer (0.5 M solution in tetrahydrofuran) (17.5 mL, 8.73 mmol) was added dropwise, and then the mixture was stirred for two hours. A 3 M sodium hydroxide solution (3.49 mL, 10.5 mmol) and 30% aqueous hydrogen peroxide (2.47 mL) were added dropwise to the reaction solution at 0° C., and then the mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with water and ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=100:1→1:2) to give 1.58 g of an isomer A (less polar isomer) of the title compound and 50.0 mg of an isomer B (more polar isomer) of the title compound as colorless syrups.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17].[CH2:20]([Li])CCC.CCCCCC.IC>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[C:5]([CH3:20])[C:4]=1[C:16]([F:18])([F:17])[F:19]
Reactant: COc1ccc(NC(=O)C(C)(C)C)cc1C(F)(F)F
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)C(C)(C)C)c(C)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
A solution of N-[4-methoxy-3-(trifluoromethyl)-phenyl]-2,2-dimethylpropanamide (5.90 g, 21.4 mmol) in tetrahydrofuran (70.0 ml) was cooled to −10 to −15° C., and then a 1.57M n-butyllithium/hexane solution (33.5 ml, 52.5 mmol) was added dropwise thereto over a period of 25 minutes while maintaining the internal temperature at 0° C. or lower. The resulting mixture was slowly warmed up to 20° C. and stirred for 3 hours while maintaining the temperature. The resulting suspension was cooled to −35 to −40° C., and then iodomethane (1.53 ml, 24.6 mmol) was added dropwise thereto over a period of 15 minutes. The resulting mixture was slowly warmed up to −5 to 0° C. and stirred for 1.5 hours while maintaining the temperature. The mixture was partitioned and extracted with water and ethyl acetate, and the organic phase was washed with a 5% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (6.23 g). The crude product was purified by a silica gel column chromatography (eluent: hexane/diisopropyl ether=1/1) to obtain N-[4-methoxy-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide (3.20 g, 50%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: C[C@@H]1COCCN1
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@@H]1COCCN1C(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-chloro-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 3, Step B) and (R)-3-methylmorpholine (EXAMPLE 12, Step B) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19ClN4O4S, 446.1; m/z found, 445 [M−H]−. HPLC (reverse phase): RT=8.54 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.04 (br s, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.56 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.56 (br s, 1H), 7.01-6.98 (m, 2H), 4.4-4.2 (br m, 1H), 3.90-3.82 (m, 1H), 3.68-3.62 (m, 1H), 3.51 (dd, J=11.5, 2.7 Hz, 1H), 3.40-3.20 (m, 3H), 1.31-1.23 (br m, 3H).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:23])[NH:9][C@H:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=2[F:22])[CH2:11][CH:12]=C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.ClC(OC1C=CC=CC=1)=[O:27]>CO.C(#N)C.CCOC(C)=O>[C:1]1([O:7][C:8](=[O:23])[NH:9][C@H:10]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:15]=2[F:22])[CH2:11][CH:12]=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C=CC[C@H](NC(=O)Oc1ccccc1)c1c(F)ccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: O=CC[C@H](NC(=O)Oc1ccccc1)c1c(F)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
(S)-Phenyl(1-(3-chloro-2,6-difluorophenyl)but-3-en-1-yl)carbamate: To a solution of crude Intermediate 17B (1.17 g, 3.64 mmol) in MeOH (10 mL) was added HCl (5 mL, 20.00 mmol) and the reaction was stirred at rt for 1 h. After 1 h, the reaction mixture was concentrated and dried under vacuum to obtain a pale yellow solid. The solid was dissolved in ACN (25 mL) followed by addition of TEA (1.520 mL, 10.91 mmol). The above reaction mixture was cooled to 0° C. To this mixture was added phenyl chloroformate (0.502 mL, 4.00 mmol) dropwise and the resulting reaction was stirred at 0° C. for 1 h. The reaction mixture was then diluted with EtOAc and washed with water followed by brine. The crude product was then purified by silica gel chromatography to give the desired product (490 mg, 40%) as clear oil. MS (ESI) m/z: 338.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]#N)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:14].[K+].C(O)C[OH:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:18])=[O:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: [OH-]
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: [K+]
Product: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C

Procedure:
1-(4-chlorophenyl)cyclobutane nitrile (5 g) was mixed with ethylene glycol (60 ml) and 40% w/w aqueous potassium hydroxide solution (80 ml) and refluxed under argon for 18 hours. The mixture was cooled, added to ice water nd extracted with diethyl ether. The aqueous layer was acidified and the precipitate was filtered off, washed with water, dried and recrystallized from petroleum ether (b.p. 40°-60°) to give the acid as white needles mp 88°-89°, yield, 4.5 g (82%).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7](I)=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2].[F:19][C:20]([F:25])([F:24])C([O-])=O.[Na+].CN1CCCC1=O>CCOCC.[Cu]I>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:20]([F:25])([F:24])[F:19])=[C:6]([CH2:11][CH3:12])[N:5]=[C:4]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCc1nc(-c2ccccc2)n(CC)c(=O)c1I
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CCc1nc(-c2ccccc2)n(CC)c(=O)c1C(F)(F)F
Yield: 42.2 %

Procedure:
A mixture of 1.00 g (2.8 mmol) of 3,6-diethyl-5-iodo-2-phenyl-4(3H)-pyrimidinone, 1.08 g (5.7 mmol) of copper (I) iodide, 1.54 g (11.3 mmol) of sodium trifluoroacetate and 8 mL of anhydrous N-methylpyrrolidinone was heated at 175 C for 2 h. The mixture was cooled, diluted with 175 mL of ether, washed with four 50 mL portions of water and dried over MgSO4. Removal of the solvent on the rotovap afforded 0.92 g of crude product as a brown oil. This material was purified by flash chromatography on a 25 g column of silica gel eluting with 100 mL portions of 0, 10, 20, 30, 40, 50 and 75% ether in hexanes to afford 0.35 g of 3,6-diethyl-2-phenyl-5-trifluoromethyl-4(3H)-pyrimidinone (compound 185) as a white solid. 1H-NMR (CDCl3) 1.25(3H,t), 1.30(3H,t), 2.8(2H,q), 4.0(2H,q), 7.5(5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[O:15][C:14](=O)[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[NH:20][C:14](=[O:15])[NH:13][C:12](=[O:18])[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1ccc(F)cc1)CC2
Reactant: [NH4+]
Agent: [OH-]
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2c1ccc(F)cc1
Temperature: 0 °C
Yield: 34.7 %

Procedure:
A solution of 7-(4-fluorophenyl)-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (13.527 g, 54.7 mmol) in concentrated ammonium hydroxide (150 mL, 3852 mmol) was heated at 100° C. in a high-pressure (350 mL) vessel overnight. The reaction mixture was cooled to 0° C. and filtered. The precipitate was consecutively washed with water and dried, first—by passing air through the filter, and then—in pump vacuum to give 7-(4-fluorophenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione (4.670 g, 18.97 mmol, 34.7% yield). LC-MS (M+H)+=247.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.70-11.81 (2H, br s), 7.31-7.39 (2H, m), 7.16-7.22 (2H, m), 4.30-4.38 (1H, m), 2.63-2.73 (1H, m), 2.53-2.63 (2H, m), 1.84-1.95 (1H, m).
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1.ClCCl.CO>O1CCCC1>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:30][CH2:31][CH2:32][CH3:33])[N:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
Benzyl isocyanate (59 μL, 0.48 mmol) was added at ambient temperature to a suspension of 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL). A solution was obtained in less than 30 minutes and thin layer chromatography (9:1 dichloromethane:methanol) showed one major new spot with a higher Rf and only a trace of starting material. Aminomethyl resin (280 mg) was added and the reaction mixture was stirred for 15 minutes. The solvent was removed under vacuum. The residue was purified by column chromatography to provide 0.16 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylurea as a white solid. Analysis: Calculated for C25H31N7O: %C, 67.39; %H, 7.01; %N, 22.00; Found: %C, 67.43; %H, 6.92; %N, 22.02.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]([NH2:16])=[S:15]>C(O)C>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:13]=[C:14]([NH2:16])[S:15][CH:2]=1
Reactant: NC(N)=S
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Product: COc1ccccc1-c1csc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
2-Bromo-1-(2-methoxy-phenyl)-ethanone (0.6388 g, 2.789 mmol) and thiourea (0.2289 g, 3.007 mmol) were dissolved in a 20 mL of ethanol. The reaction mixture was allowed to stir overnight at room temperature. The ethanol was evaporated to dryness and the crude product was dissolved in a minimum of dichloromethane. The crude product was then extracted twice with 1M sodium hydroxide and once with a saturated aqueous solution of sodium chloride. The organic layer was then dried over sodium sulfate, filtered, and evaporated to dryness to yield the pure product (0.529 g, 2.56 mmol, 92.0%). ESI-MS m/z calc. 206.3. found 207.1 (M+1)+ Retention time 1.86 minutes. 1H NMR (400 MHz, CD3CN) δ 3.91 (s, 3H), 5.54 (s, 2H), 6.97-7.02 (m, 1H), 7.03-7.06 (m, 1H), 7.23 (s, 1H), 7.24-7.29 (m, 1H), 8.06 (dd, J=7.8, 1.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([O:24]CC)=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][NH2:28].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:13]([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[N:12]=[C:11]([C:22]([NH:28][CH3:27])=[O:24])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: CCOC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Solvent: CO
Product: CNC(=O)c1cc(Sc2cccc(Br)c2)n(-c2cc(F)ccc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of ethyl 5-[(3-bromophenyl)thio]-1-(2,5-difluorophenyl)-1H-pyrazole-3-carboxylate (2.04 g) in methanol (2 mL) was added 40% methylamine-methanol solution (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=2:1) to give the title compound as a yellow oil (yield 1.35 g, yield 76%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]2[C:10]([N:15]=1)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:5][CH3:6].[C:16]1([C:22]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=3)=[N:26][N:25]=[N:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:3]([CH:7]1[N:15]([CH2:40][C:37]2[CH:36]=[CH:35][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]3[N:23]([C:22]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:24]=[N:25][N:26]=3)=[CH:39][CH:38]=2)[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8]1)[CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc2ncccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC1Nc2cccnc2N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (102 mg of an 80% dispersion, 3.39 mmol) in dry dimethylformamide (6 mL) at rt was added 2-butylimidazo[4,5-b]pyridine (495 mg, 2.83 mmol) in one portion. After 20 minutes, the mixture was cooled to 0° C. and N-triphenylmethyl-5-(4'-bromomethylbiphenyl-2-yl)tetrazole (1.50 g, 2.70 mmol) was added in one portion. The resulting dark colored mixture was warmed to rt and stirred for 15 hours. The excess NaH was quenched with water (1 mL) and the bulk of the DMF was removed in vacuo at 40°-50° C. Extraction with EtOAc (4×20 mL) from brine (60 mL), drying (K2CO3), and concentration gave a thick dark oil. Purification by flash chromatography (SiO2, solvent gradient: 80% EtOAc/hexanes, 100% EtOAc) gave 417 mg (23%) of 2-butyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-1H-imidazo[ 4,5-b]pyridine as a thick oil: Rf=0.75 (SiO2, 100% EtOAc), 1H NMR (300 MHz, CDCl3) δ8.35 (1H, dd, J=6, 1 Hz), 8.05 (1H, dd, J=9, 1 Hz), 7.92 (1H, dd, J=9, 1.5 Hz), 7.51-7.42 (3H, m), 7.36-7.20 (11H, M), 7.07 (2H, d, 7 Hz), 6.96-6.89 (7H, m), 5.40 (2H, s), 2.73 (2H, t, J=7.5 Hz), 1.84-1.70 (2H, m), 1.41-1.30 (2H, m), 0.88 (3H, t, J=7.5 Hz).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1>CN(C)C1C=CN=CC=1.CC(O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C@H:2]([OH:1])[CH2:3][N:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc([C@H]2CO2)cc1
Reactant: CCOC(=O)[C@H]1CCCNC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CCCN(C[C@@H](O)c2ccc(C#N)cc2)C1
Temperature: 55 °C

Procedure:
(S)-4-(Oxiran-2-yl)benzonitrile (10.00 g, 68.9 mmol), (S)-ethyl piperidine-3-carboxylate (10.83 g, 68.9 mmol) and iPrOH (100 mL) was charged into a round bottom flask under N2. After heating at 55° C. for 4 hours, 4-dimethylaminopyridine (1.683 g, 13.78 mmol) was then added. The reaction mixture was then heated to 50° C. for an additional 12 hours. At this time HPLC indicated the starting material was completely converted to the desired product. The reaction mixture was then cooled to room temperature. EtOAc (120 ml) was added, followed by 100 ml of water. The organic layer was separated, extracted with EtOAc (2×100 mL) and concentrated under vacuo to give a crude product. The crude product was recrystallized from EtOH/EtOAc/H2O (3/2/2) (8 ml/1 g) to give a crystalline off-white solid 14A-alt (15 g, 72% yield, 99.6% e.e.). The absolute and relative stereochemistry was determined by single X-ray crystallography employing a wavelength of 1.54184 Å. The crystalline material had an orthorhombic crystal system and unit cell parameters approximately equal to the following:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH2:18]1[C:21]2([CH2:25][CH2:24][CH2:23][NH:22]2)[CH2:20][O:19]1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:22]2[CH2:23][CH2:24][CH2:25][C:21]32[CH2:18][O:19][CH2:20]3)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: C1CNC2(C1)COC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1CN1CCCC13COC3)CCCN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (Intermediate 41) (0.19 g, 0.78 mmol) in DCM (10 mL) was added 2-oxa-5-azaspiro[3.4]octane (0.248 g, 1.57 mmol), DIPEA (0.410 mL, 2.35 mmol) and sodium triacetoxyborohydride (0.332 g, 1.57 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was added slowly to water (10 ml). The aqueous was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure to afford the title compound. (UPLC-MS 3) Rt=0.55 min; MS m/z [M+H]+ 334.
Reaction SMILES: [Sr:1].[CH3:2][O:3][CH2:4][CH2:5][OH:6]>>[CH3:2][O:3][CH2:4][CH2:5][O-:6].[Sr+2:1].[CH3:2][O:3][CH2:4][CH2:5][O-:6]
Reactant: [Sr]
Reactant: COCCO
Product: COCC[O-]
Product: [Sr+2]

Procedure:
The strontium was placed in about 80 ml 2-methoxyethanol and reacted to produce strontium 2-methoxyethoxide and evolving hydrogen gas. The 2-ethylhexanoic acid was added, and the mixture stirred and heated to a maximum temperature of about 118° C. to produce strontium 2-ethylhexanoate and distill off all water. The bismuth 2-ethylhexanoate was combined with 50 ml xylenes, and the mixture stirred and heated to a maximum temperature of about 125° C. to distill off all water. The titanium isopropoxide was combined with about 50 ml 2-methoxyethanol, and the mixture was stirred and heated to a maximum temperature of about 116° C. to produce titanium 2-methoxyethoxide and distill off all isopropanol and water. The strontium 2-ethylhexanoate and bismuth 2-ethylhexanoate solutions were combined (total 90 ml) and stirred and heated to a maximum of about 125° C. to distill down to 50 ml. About 40 ml xylenes were added, and the mixture was stirred and heated to a maximum temperature of about 125° C. to distill down to 50 ml again. The titanium 2-methoxyethoxide was added, and the mixture was stirred and heated to a maximum temperature of about 125° C. to distill down to 60.0 ml with a concentration of 0.101 moles of SrBi4Ti4O15 per liter.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:1][CH:2]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of p-cresol (2 mL, 19.1 mmol) in anhydrous DMF (50 mL) were added Cs2CO3 (8.1 g, 24.9 mmol) and methyl bromoacetate (1.9 mL, 20.1 mmol). The suspension was stirred at room temperature for 3 h. After dilution with ethyl acetate, the reaction mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The resulting oil was purified by chromatography on silica gel (Hexane/ethyl acetate 8/2) to afford the title compound as a colorless oil (3.10 g, 90%).