Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][C:20]1[O:24][CH:23]=[CH:22][CH:21]=1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(Cc1ccco1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(Cc1ccco1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 72.1 %

Procedure:
3.6 g of 1-(2-chloroethyl)-3-furfuryl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-furfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br>>[ClH:1].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][N:28]([CH2:36][C:35]5[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=5[C:33]([F:32])([F:42])[F:43])[CH2:29][CH2:30]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Agent: Cl
Product: O=C(CCC1CCN(Cc2ccccc2C(F)(F)F)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, and 2-(trifluoromethyl)benzyl bromide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:25]([N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:15]=[CH:16][C:17]=2[CH2:23]1)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2ccncc2)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a mixture of N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (94.8 mg, 0.30 mmol) and isonicotinoyl chloride hydrochloride (56.1 mg, 0.32 mmol) in THF (2.0 mL) at room temperature was added N,N-diisopropylethylamine (0.157 mL, 0.90 mmol). After stirring for 3 hours at room temperature, an additional 21 mg of isonicotinoyl chloride hydrochloride was added and the reaction continued for 17 hours. The reaction was quenched with H2O, then treated with an EtOAc/saturated NaHCO3(aq) solution work-up to give an off-white solid. The solid was recrystallized from EtOAc/hexane to afford a white solid (115 mg, 91%).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](Cl)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>O1CCCC1>[C:8]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])=[O:23])=[CH:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)Cl)ccc12
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Triethylamine (50 μl, 0.36 mmol) and 5-(acetyloxy)naphthalene-2-sulfonyl chloride (84.9 mg, 0.30 mmol) were added to benzylamine (32.1 mg, 0.30 mmol) dissolved in tetrahydrofuran (3 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane: ethyl acetate=2:1→1:1) to give the title compound as a light yellow white crystal (72.1 mg, 67.6%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH2:14][CH2:15][C:16]2=O)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](C1C=CC=CC=1[Se]C#N)([O-])=[O:26].C(P(CCCC)CCCC)CCC.OO.Cl>O1CCCC1.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH:17]2[CH:13]([CH:14]([OH:26])[CH:15]=[CH:16]2)[CH:12]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C2CCC(=O)C2CN1C(=O)OCc1ccccc1
Reactant: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: CCCCP(CCCC)CCCC
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C1C2C(O)C=CC2CN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of the compound prepared as described in Example 3 (6.89 g) and 2-nitrophenyl selenocyanate (4.72 g) in tetrahydrofuran (100 ml) was cooled to about -20° C. under a nitrogen atmosphere. The cooled solution was treated with tributylphosphine (5.2 ml) in one portion. After one hour, the reaction solution was treated with pyridine (100 ml) and the resulting mixture allowed to warm to room temperature. The reaction was then treated with 30% hydrogen peroxide (35 ml). After an additional two hours, the reaction mixture was added to 1N hydrochloric acid (200 ml), and the title compound was extracted with diethyl ember. The diethyl ether extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC, eluting with a linear gradient of hexane to hexane/ethyl acetate (1:1), to give 4.97 g of compound 7.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:10]([CH2:13]C(=O)C)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][CH2:11][C:10](=[O:12])[CH3:13]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1ccccc1F
Yield: 65.8 %

Procedure:
A stirred mixture of 2-fluorobenzyl chloride (22.47 g), acetylacetone (17.10 g), anhydrous potassium carbonate (21.5 g) and ethanol (155 ml) was heated at reflux for 18 hr. The solvent was evaporated and the residue was partitioned between water (200 ml) and ether (150 ml). The aqueous layer was washed with ether (3×150 ml). The extracts were combined, washed with brine (200 ml), dried (MgSO4) and evaporated. Distillation of the residue under reduced pressure gave the product (17 g) b.p. 58°-66°/0.5-0.6 mm.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CS(C)=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: BrCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1 g of caffeic acid was dissolved in 25 mL of dimethylsulfoxide. 0.77 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 1.10 mL of phenethyl bromide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 75 mL of cold water and extracted with ethyl acetate (3×60 mL). The combined organic extract was washed with 50 mL of 5% HCl and water (60 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from toluene by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 760 mg and the purity was greater than 90%.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH:24]=[CH:23][CH:22]=4)[C:18]([C:31]4[N:36]=[CH:35][CH:34]=[CH:33][N:32]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Br:37]N1C(=O)CCC1=O>CN(C)C=O>[Br:37][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:20]=[C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[C:18]([C:31]3[N:32]=[CH:33][CH:34]=[CH:35][N:36]=3)=[CH:17][CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1cnc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2-c2cccc3ccccc23)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1c2ccccc2c(-c2ccc(-c3ncccn3)c(-c3cccc4ccccc34)c2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Dissolving 8.5 g (19 mmol) of 4-anthracen-9-yl-6-naphthalen-1-yl-phenyl-pyrimidine obtained in the foregoing step (2) into 100 milliliter of N,N-dimethylformamide, and adding 3.6 g (20 mmol) of N-bromosuccinimide, stirred at room temperature for 8 hours. After completion of the reaction, precipitated solids were separated by filtration and washed with water and methanol, thereby obtaining 7.2 g of 4-(10-bromo-anthracen-9-yl)-6-naphthalen-1-yl-phenyl-pyrimidine (yield: 73%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:19]=[CH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.C([O-])(=O)C.[K+].[CH3:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1>C(#N)C.O.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>[CH3:34][C:35]1[C:40]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][CH2:7][CH2:8][C:9]4[CH:15]=[C:14]([C:16]5[N:20]([C:21]6[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=6[F:28])[N:19]=[CH:18][N:17]=5)[S:13][C:10]=4[C:11]=3[N:12]=2)=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: Cc1ncccc1B(O)O
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncccc1-c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Yield: 70 %

Procedure:
5-(2-(Chloro)-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (50 mg, 0.1 mmol) was dissolved in 1 ml acetonitrile and 1 ml water, with potassium acetate (39.9 mg, 0.406 mmol). The solution was degassed by bubbling with nitrogen for 5 min. 2-Methylpyridin-3-ylboronic acid (21.4 mg, 0.156 mmol) was added, then tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes, cooled to room temperature, and extracted with ethyl acetate. The combined organics were concentrated and purified by reverse phase HPLC to give 474 (70% yield). MS: (ESI+)=474.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.Cl.[CH2:33]([N:35]=C=NCCCN(C)C)[CH3:34].ON1C2C=CC=CC=2N=N1.C(N)C>O.CN(C)C=O>[CH2:33]([NH:35][C:18](=[O:19])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1)[CH3:34]
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CCN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (90 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 30 min, and then ethylamine (2M solution in tetrahydrofuran, 0.43 mL) was added to the mixture. The whole was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residual crystals were washed with ethyl acetate-hexane and collected by filtration to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (130 mg, 62%) as colorless prisms. MS 489 (MH+). mp 236-237° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)=[CH:5][CH:4]=1.[OH:29]OS([O-])=O.[K+].C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[N:22]=3)=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)=[CH:5][CH:4]=1)=[O:29]
Reactant: O=S([O-])OO
Reactant: COc1nccc(-c2[nH]c(-c3ccc(SC)cc3)nc2-c2ccc(F)cc2)n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nccc(-c2[nH]c(-c3ccc(S(C)=O)cc3)nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a solution of 2-(4-methylthiophenyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole (0.10 g, 0.25 mmol) in 10 mL of THF at 0° C. was added a cooled solution of Oxone (0.084 g, 0.28 mmol)in 10 mL of H2O. The solution was warmed to room temperature and stirred for 20 min. Next, 20 mL of NaHCO3 sat was added and the mixture was extracted thrice with 20 mL of CH2Cl2. The combined organic layers were washed with 20 mL of 20% NaS2O5 and brine and then dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was then purified by silica gel chromatography with 2-6% CH3OH/CH2Cl2 to give the title compound as a light yellow solid (0.084 g, 82%). ES(+) MS m/e=409 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1Cl
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(Cl)cc3Cl)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.6 %

Procedure:
2,4-Dichloroaniline (0.383 g, 2.366 mmol), triethylamine (0.239 g, 2.366 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.400 g, 2.366 mmol) were added to a methylene chloride solution (100 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.295 g, 0.789 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.150 g, 0.289 mmol, 37%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.CCN(CC)CC.[CH2:19]([NH2:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCCCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in EtOAc (50 mL) were added Et3N (2.43 g, 24 mmol) and hexan-1-amine (2.02 g, 20 mmol). The reaction mixture was refluxed overnight, then cooled to rt and concentrated in vacuo to give the title compound as yellow oil (4.37 g, 91%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)[OH:17].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:24][C:20]1[CH:19]=[C:18]([C@@H:16]([OH:17])[CH2:15][NH:14][C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(O)cc1)NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
To a mixture of 3-(4-hydroxyphenyl)propanoic acid (15.0 g), (1R)-2-amino-1-(3-chlorophenyl)ethanol hydrochloride (18.8 g), and 1-hydroxybenzotriazole (14.6 g) in N,N-dimethylformamide (100 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26.0 g), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed successively with sodium bicarbonate solution and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-3-(4-hydroxyphenyl)propanamide (11.61 g) as a white amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:22]([O:32][CH2:33][CH3:34])=[N:21]4)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[Cl:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[C:23]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:22]([O:32][CH2:33][CH3:34])=[N:21]4)[CH:16]=[CH:15][N:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccnc(OCc3cn4c(Cl)cccc4n3)c2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
After a mixture of ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionate (605 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[2-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazol-4-yl]propionic acid (534 mg, yield: 94%). This was recrystallized from ethanol-hexane. Melting point: 160–161° C.
Reaction SMILES: [CH:1]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[NH:31][N:30]=NN=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:5]3)[CH2:2]1)[CH2:9]2.[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>O>[CH:8]12[CH2:7][CH:6]3[CH2:11][CH:1]([CH2:2][CH:3]([N:4]([CH2:12][CH2:13][C:14]([C:27]4[O:34][C:32]([CH3:33])=[N:30][N:31]=4)([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:5]3)[CH2:10]1)[CH2:9]2
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2nnn[nH]2)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nnc(C(CCN2CC3CC4CC(C3)CC2C4)(c2ccccc2)c2ccccc2)o1

Procedure:
A solution of 48 parts of 5-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-1H-tetrazole and 140 parts of acetic anhydride in 400 parts of pyridine is heated at the boiling point under reflux for 3 hours, then cooled and thereupon diluted with 100 parts of water. The resultant mixture is stirred for 10 minutes, whereupon solvent is removed by vacuum distillation and the residue partitioned between a saturated aqueous solution of sodium bicarbonate and diethyl ether. The ethereal phase is separated and consecutively washed with a saturated aqueous solution of sodium bicarbonate and water, then extracted with 2% hydrochloric acid. The acid extract is made alkaline, and the resultant mixture is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate, stripped of solvent by vacuum distillation, affords 2-{3-[4-azatricyclo(4.3.1.13,8)undecan-4-yl]-1,1-diphenylpropyl}-5-methyl-1,3,4-oxadiazole melting at approximately 120°-121° as the residue. It has the formula ##STR11##
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][CH2:16][C:17]([OH:19])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH2:21]([N:28]1CCC(OCC(OC)=O)CC1)[C:22]1C=CC=CC=1.C(N)C>CO>[CH2:21]([NH:28][C:17](=[O:19])[CH2:16][O:15][CH:12]1[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[CH3:22]
Reactant: COC(=O)COC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)COC1CCN(Cc2ccccc2)CC1
Agent: CCN
Agent: Cl
Solvent: CO
Product: CCNC(=O)COC1CCN(Cc2ccccc2)CC1

Procedure:
2-(1-Benzylpiperidin-4-oxy)acetic acid, hydrochloride, prepared similarly to Preparation L Part A, was converted to its methyl ester by refluxing in methanol plus concentrated hydrochloric acid. Methyl 2-(1-benzylpiperidin-4-oxy)acetate (10 g) and ethylamine (50 ml) with 3 A molecular sieves were heated in a bomb at 120° for 6 hours. The solvent was then evaporated in vacuo, the residue triturated with ether, filtered and the filtrate evaporated to give N-ethyl-2-(1-benzylpiperidin-4-oxy)acetamide (7.7 g) as an oil. This product (7.0 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal (Engelhardt special debenzylation catalyst) at 50° and 50 p.s.i.