Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[F:10][C:11]([F:25])([F:24])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20])=[CH:14][CH:13]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.O1CCCC1>[F:10][C:11]([F:24])([F:25])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH:21]([CH3:23])[CH3:22])([CH2:27][CH2:28][CH2:29][Cl:30])[C:19]#[N:20])=[CH:16][CH:17]=1
Reactant: ClCCCBr
Reactant: CC(C)C(C#N)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCCl)c1ccc(C(F)(F)F)cc1
Yield: 89.2 %

Procedure:
To a solution consisting of a 0.5 M solution of bis(trimethylsilyl)amide in toluene (2.2 mL, (1.1 mmoles) and tetrahydrofuran (7.8 mL) stirring at −78° under an argon atmosphere was added dropwise a solution of the compound of Example 7, Step (a) (227 g, 1.00 mmole) in tetrahydrofuran (1.0 mL). After stirring for 1.0 hour at −78°, 3-bromo-1-chloropropane (236 mg, 1.50 mmoles) was added in one portion, and the resulting mixture was stirred for 30 minutes at −78° and then 2.0 hours at room temperature. The mixture was partitioned between diethyl ether and water, the aqueous layer was extracted with ether, and the combined organic extracts were washed with water and then brine. After drying over sodium sulfate, the solution was filtered and then evaporated. A compound (271 mg) was obtained as a red oil which was characterized by NMR as follows: 1H NMR(CDCl3) d 7.65(d, 2H), 7.53(d, 2H), 3.48(m, 2H), 1.19(d, 3H), 0.79(d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[C:6]([Br:12])[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1.[CH3:24]/[C:25](/[NH2:29])=[CH:26]\[C:27]#[N:28].[CH2:30]([CH:33]1[CH2:38][C:37](=[O:39])[CH2:36][C:35](=O)[CH2:34]1)[CH2:31][CH3:32]>C(O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH:10]2[C:36]3[C:37](=[O:39])[CH2:38][CH:33]([CH2:30][CH2:31][CH3:32])[CH2:34][C:35]=3[NH:29][C:25]([CH3:24])=[C:26]2[C:27]#[N:28])[CH:7]=[C:6]([Br:12])[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1
Reactant: CCCC1CC(=O)CC(=O)C1
Reactant: C/C(N)=C\C#N
Reactant: COC(=O)c1cc(C=O)cc(Br)c1OCc1cccc(OC)c1
Solvent: CCO
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCc2cccc(OC)c2)c(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-bromo-5-formyl-2-(3-methoxy-benzyloxy)-benzoic acid methyl ester (3.78 g), 3-aminocrotonitrile (822 mg) and 5-propylcyclohexane-1,3-dione (1535 mg) in ethanol (25 ml) was stirred at 80° C. for 17 h. The mixture was concentrated in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:18])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.Br[CH:20]([CH3:28])[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:20]([CH3:28])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:7]=1
Reactant: N=C(Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Br)cc2)c1C
Temperature: 100 °C
Reaction time: 12 h
Yield: 47.2 %

Procedure:
To a magnetically stirred solution of above imidamide from step A (2.45 g, 7 mmol) in 30 mL anhydrous toluene were added ethyl 3-bromo-2-oxobutanoate (1.48 g, 7 mmol) and Na2CO3 (0.74 g, 7 mmol). The contents were stirred at 100° C. for 12 hours. The reaction was brought to RT. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. Purification by column chromatography gave the ester as pale white solid (1.5 g, 46.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:5][CH:4]=1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CO>[CH:23]1([NH:19][C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=3)[C@@H:10]([CH3:20])[CH2:11]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCC1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C

Procedure:
To (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (200 mg, 0.67 mmol) in MeOH was added cyclopentanone (0.073 mL, 0.74 mmol) followed Na(OAc)3BH (284 mg, 1.34 mmol) and catalytic amount of HOAc. The reaction mixture was stirred at room temperature over night. The reaction wash quenched by adding water. And the mixture was extracted with EtOAc 3 times. The organic layers were combined then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine in decent yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([C:25]([CH3:35])([CH3:34])[CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.S1C=CC2C(N3CCN(CCCCOC4C=C5C(C(C)(C)CC(=O)N5)=CC=4)CC3)=CC=CC1=2.N1C=CC=CC=1.Cl[C:76]([O:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])=[O:77]>C(Cl)Cl.O>[CH2:79]([O:78][C:76](=[O:77])[O:32][CH2:31][N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:14][CH2:15][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:11][CH2:12]3)[CH:30]=2)[C:25]([CH3:35])([CH3:34])[CH2:26][C:27]1=[O:33])[CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH2:86][CH2:87][CH3:88]
Reactant: CCCCCCCCCCOC(=O)Cl
Reactant: CC1(C)CC(=O)N(CO)c2cc(OCCCCN3CCN(c4cccc5sccc45)CC3)ccc21
Agent: CC1(C)CC(=O)Nc2cc(OCCCCN3CCN(c4cccc5sccc45)CC3)ccc21
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)OCN1C(=O)CC(C)(C)c2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 34.1 %

Procedure:
7-[4-(4-Benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (460 mg), which is a mixture with 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one obtained in Example 155, was suspended in methylene chloride (10 ml), pyridine (0.06 ml) and decyl chloroformate (103 mg) were added, and the mixture was stirred under ice-cooling for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=2:1) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)-butoxy]-4,4-dimethyl-2-oxo-3,4-dihydro-2H-quinolin-1-ylmethyl ester decyl ester (108 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[C:4](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:5]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:7][Si](C)(C)C)[CH:6]=1.C(O)(=O)C.O1CCCC1.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[C:3](=[O:30])[C:4](=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:5]([OH:7])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:6]=1
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC1(O)C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 2 h
Yield: 97 %

Procedure:
31 g of the mixture of E- and Z-isomes of 2-chloro-5-(6-methoxycarbonylhexylidene)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 2 was mixed with 3 ml of a 6:1:3 mixture of acetic acid, tetrahydrofuran and water, and the mixture was stirred for 2 hours. A saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ether. The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was chromatographed on a silica gel column to give 25 mg (yield 97%) of a mixture of Z- and E-isomers of 2-chloro-4-hydroxy-5-(6-methoxxycarbonylhexylidene-4-octyl-2-cyclopentenone.
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[ClH:18]>O1CCCC1>[Cl:18][C:1]1[NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
To a solution (60 mL) of ethyl 2-cyano-4-oxo-4-phenylbutanoate (5.0 g) in tetrahydrofuran was blown in hydrogen chloride (28 g) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. Then, nitrogen was blown in to remove excess hydrogen chloride. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1) to give the title compound as a pale-yellow solid (yield 4.24 g, 79%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC(COCCCCCCCCCCCC)CN1CCNCC1.[F:54]C1C=CC(CCl)=CC=1>[Pd]>[F:54][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([OH:30])[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc(CCl)cc1
Agent: [Pd]
Agent: CCCCCCCCCCCCOCC(O)CN1CCNCC1
Product: CCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccc(F)cc2)CC1

Procedure:
Following the procedures of Examples 4 and 5, 1-benzyl-4-(2-hydroxy-3-n-dodecyloxypropyl)-piperazine was converted to 1-(2-hydroxy-3-n-dodecyloxypropyl)piperazine by hydrogenolysis using a palladium on carbon catalyst. The hydrogenolysis product was reacted with 4-fluorobenzyl chloride to form 1-(4-fluorobenzyl)-4-(2-hydroxy-3-n-dodecyloxypropyl)-piperazine, mp 243°-245° C.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:53])[CH2:51][CH3:52].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:46]([N:5]1[C:4](=[O:49])[CH:3]=[C:2]([S:53][CH2:50][CH2:51][CH3:52])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]1=[O:45])[CH2:47][CH3:48]
Reactant: CCCS
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 56 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (1 g), propylmercaptan (0.17 ml) and potassium carbonate (0.25 g) in acetonitrile (10 ml) was heated under reflux for 3 hours with stirring. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (30 ml) and then 1N hydrochloric acid (3.0 ml) was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless powders (0.4 g, 56%).
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[Cl:18])[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][N:7]=1.C(N(C(C)C)C(C)C)C.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([NH2:46])([CH3:45])[CH3:44])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1.O>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:8]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH:46][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:45])[CH3:44])[C:3]2=[O:19])[CH:9]=1
Reactant: CC(C)(N)c1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(Cl)c(-n2ccnc(Br)c2=O)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc(Cl)c(-n2ccnc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Temperature: 125 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A solution of methyl 3-(3-bromo-2-oxopyrazin-1(2H)-yl)-4-chlorobenzoate (Example 330e, 3 g) dissolved in toluene (15 mL) was treated with N-ethyldiisopropylamine (2.99 mL) and 2-(2-(benzyloxy)phenyl)propan-2-amine (Example 198d 2.107 g) under nitrogen. The resulting mixture was stirred at 125° C. for 8 h in a sealed tube. The reaction mixture was diluted with water (150 mL), and extracted with ethyl acetate (250 mL). The organic was dried (MgSO4), filtered and evaporated to afford crude product. Purification (SiO2 chromatography eluting with 50% diethyl ether in isohexane) gave the subtitle compound (2.230 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([Br:17])[C:7]=1O)=[O:5])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].S([O:30][CH3:31])(OC)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:19])=[C:8]([Br:17])[C:7]=1[O:30][CH3:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(O)c(Br)c(O)c2ccccc12
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(OC)c(Br)c(OC)c2ccccc12
Yield: 98.8 %

Procedure:
To a solution of ethyl-3-bromo-2,4-dihydroxy-1-naphthoate (5.8 g, 18.6 mmol) in acetone (93 mL) was added potassium carbonate (6.43 g, 46.6 mmol) and dimethyl sulfate (4.4 mL, 46.6 mmol). The mixture was heated under reflux overnight and solvent was removed in vacuo. Water and EtOAc was added and the organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography (eluting with 3-5% EtOAc/hexane) to give the product (6.23 g, 99% yield) as a light yellow oil. 1H NMR (CDCl3) δ 8.13 (d, 1H), 7.83 (d, 1H), 7.62-7.48 (m, 2H), 4.54 (q, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:3][CH2:2]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1N1CCOCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A mixture of 2-morpholinophenol (100 mg, 0.56 mmol) and ethyl 2-bromoacetate (200 mg, 0.672 mmol) in CH3CN (10 mL) was added K2CO3 (772.8 mg, 5.6 mmol). The reaction mixture was stirred at 80° C. for 4 h. The solid was removed by filtration and the filtrate concentrated to give a crude material, which was used in the next step without further purification. (130 mg, Yield 90%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:26]#[N:27])[C:10]([CH3:25])=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:13]3[CH2:17][CH2:16][C:15](=O)[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1.[CH3:28][NH:29][CH3:30].C(O)(=O)C.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[NH3:8].[CH3:4][OH:5].[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:26]#[N:27])[C:10]([CH3:25])=[C:11]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:12]=3[C@@H:13]3[CH2:17][CH2:16][C@@H:15]([N:29]([CH3:30])[CH3:28])[CH2:14]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccccc2)c(C2CCC(=O)C2)c2oc(C3CC3)nc2c1C#N
Reactant: CNC
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(-c2ccccc2)c([C@@H]2CC[C@@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Product: N
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.5 %

Procedure:
2-Cyclopropyl-5-methyl-7-(3-oxocyclopentyl)-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-303) (44 mg, 0.12 mmol) was dissolved in chloroform (1 ml) and methanol (1 ml), and at 0° C., dimethylamine (2 M tetrahydrofuran solution) (247 μl, 0.49 mmol), acetic acid (29 μl, 0.49 mmol) and sodium cyanoborohydride (33 mg, 0.49 mmol) were added. The solution was gradually warmed up to room temperature, then stirred for 21 hours, and fractionated with chloroform and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away and the resulting residue was purified by preparative TLC (eluent, chloroform:7 N ammonia/methanol solution=97:3, v/v) to obtain 2-cyclopropyl-7-[(1R*,3R*)-3-(dimethylamino)cyclopentyl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#141) (9.6 mg, 20%) as a white solid. Next, 2-cyclopropyl-7-[(1R*,3S*)-3-(dimethylamino)cyclopentyl]-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (#142) (26 mg, 55%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:27]#[N:28])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:12]([C:23]([F:26])([F:25])[F:24])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].Cl.[N:30]([O-])=O.[Na+]>O1CCOCC1.O>[CH3:22][O:21][CH2:20][CH2:19][O:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:5]2[N:4]=[C:3]([C:27]#[N:28])[C:2]3[N:1]=[N:30][N:8]([CH3:9])[C:7]=3[CH:6]=2)=[CH:11][C:12]=1[C:23]([F:26])([F:24])[F:25]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCOCCOC)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COCCOCOc1ccc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
3-amino-6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)phenyl)-4-(methylamino)picolinonitrile (100 mg) was suspended in dioxane (1500 μl) and water (1500 μl) and cooled to 0° C. Hydrochloric acid (2M, 189 μl) followed by dropwise addition of sodium nitrite (25 mg) in water (500 μl) and the mixture stirred at room temperature for 2 hours. The suspension was filtered and the solid washed with water to afford pale brown solid 6-(4-((2-methoxyethoxy)methoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (92% yield).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[S:4][N:3]=1.C1N=CN([C:26](N2C=NC=C2)=[O:27])C=1.[C:33]1([CH:39]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][CH2:41][NH:42][CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:33]1([CH:39]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH2:40][CH2:41][N:42]([CH2:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=2)[C:26](=[O:27])[NH:1][C:2]2[N:6]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[CH:11][CH:12]=3)[S:4][N:3]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(C(CCNCCc2ccccn2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2nc(N)ns2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(NC(=O)N(CCc3ccccn3)CCC(c3ccccc3)c3ccccc3)ns2)cc1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl 4-(3-amino-1,2,4-thiadiazol-5-yl)phenylcarbamate (0.078 g, 0.27 mmol), DMAP (0.049 g, 0.40 mmol), and CDI (0.066 g, 0.41 mmol) was added DMF (1 mL). The reaction mixture was heated to 50° C. for 15 h and 3,3-diphenyl-N-(2-(pyridin-2-yl)ethyl)propan-1-amine (0.090 g, 0.28 mmol) was added. The reaction mixture was heated to 50° C. for 20 h. Direct purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave tert-butyl 4-(3-(3-(3,3-diphenylpropyl)-3-(2-(pyridin-2-yl)ethyl)ureido)-1,2,4-thiadiazol-5-yl)phenylcarbamate 156.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH2:17]=[C:18]1[C:23](=[O:24])[CH:22]2[CH2:25][CH2:26][N:19]1[CH2:20][CH2:21]2>CC(C)=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]([CH2:17][CH:18]2[C:23](=[O:24])[CH:22]3[CH2:25][CH2:26][N:19]2[CH2:20][CH2:21]3)[C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: C=C1C(=O)C2CCN1CC2
Reactant: CC(=O)CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: CC(=O)C(CC1C(=O)C2CCN1CC2)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Product: Cl

Procedure:
In a manner similar to Example XXV react 1-(4-chloro-3-nitrophenyl)-1,3-butanedione with 2-methylene-3-quinuclidinone in acetone to provide the title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][CH2:16][NH:17][C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[O:19])[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[C:26](OC1C=C(CCNC(C2C=NC=CC=2)=O)C=CC=1OC(=O)C(C)(C)C)(=O)C(C)(C)C.C[I:58]>CO>[I-:58].[CH3:26][N+:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18](=[O:19])[NH:17][CH2:16][CH2:15][C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH:21]=1
Reactant: CC(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(C)=O
Reactant: CI
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C
Solvent: CO
Product: CC(=O)Oc1ccc(CCNC(=O)c2ccc[n+](C)c2)cc1OC(C)=O
Product: [I-]

Procedure:
To a solution of 1.71 g (5 mmol) of 3-{N-[β-(3,4-diacetoxyphenyl)ethyl]}carbamoylpyridine (prepared like compound 8c), 1.41 g (10 mmol) of methyl iodide were added and the mixture was refluxed overnight under stirring. The acetone solution was then decanted from the insoluble oily residue. Ether was added to the acetone solution and the solid which separated was crystallized from acetone/ether. Yield, 1.9 g (78%) of yellow crystalline needles, m.p. 171°-173° C. U.V. (methanol) 215, 265 nm; NMR (D2O) δ 8.86-7.63 (ms, 4H, C5H4N+), 6.66 (bs, 3H, C6H3), 4.4 (s, 3H, --N+ --CH3), 3.50 (t, 2H, --N--CH2), 3.03 (t, 2H, CH2), 2.21 (bs, 6H, 2COCH3). Anal. Calcd for C19H21IN2O5 : C, 47.12; H, 4.37; N, 5.78. Found: C, 47.23; H, 4.38; N, 5.78.