Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]=1.[F:21][C:22]([C:25]1[NH:29][N:28]=[N:27][N:26]=1)([F:24])[F:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][N:4]=[C:3]([CH2:2][N:27]2[N:28]=[N:29][C:25]([C:22]([F:24])([F:23])[F:21])=[N:26]2)[N:8]=1
Reactant: FC(F)(F)c1nnn[nH]1
Reactant: CCOC(=O)c1cnc(CBr)nc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 6 h

Procedure:
An amount of 345 mg (0.97 mmol) of ethyl 2-(bromomethyl)-4-(2-chlorophenyl)pyrimidine-5-carboxylate was added to a solution of 200 mg (1.45 mmol) of trifluoromethyltetrazole in 10 ml of acetonitrile. Then 174 mg (1.26 mmol) of potassium carbonate were added to the reaction solution, which was stirred at 60° C. for 6 hours. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The residue was admixed with 10 ml of water and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by chromatography.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][NH:15]2)=[CH:11][CH:10]=1.CCN(CC)CC>>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:21]1[CH2:20][CH2:19][CH:18]([C:13]2[C:12]3[C:16](=[CH:17][C:9]([F:8])=[CH:10][CH:11]=3)[NH:15][N:14]=2)[CH2:23][CH2:22]1)[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 85 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
To a suspension of ethyl 2-bromoacetate (0.55 g, 3.3 mmol) and 6-fluoro-3-piperidin-4-yl-1H-indazole (0.60 g, 2.7 mmol in 10 mL of acetonitrile) was added Et3N (1.4 g, 13.7 mmol) and the reaction mixture was stirred at 85° C. for 15 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was redissolved in DCM (50 mL), washed with water, brine, dried over Na2SO4 and concentrated in vacuo. Purification by flash chromatography gave the title compound (0.29 g, 0.90 mmol) as a white solid. MS (ESI) m/z 306.9 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.54 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[OH:10])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[C:8]([O:11][CH3:12])[C:9]=1[O:10][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Yield: 78.3 %

Procedure:
The compound was prepared according to general procedure E with 3-fluoro-4-hydroxy-5-methoxybenzaldehyde (1.8 mmol) in dry acetone (20 ml), anhydrous K2CO3 (2.4 mmol), and ethylbromoacetate (2.7 mmol) at reflux for 1 h. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 395 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 361 mg of purified compound were obtained (79% yield). 1H NMR (500 MHz, CD3COCD3): δ 1.25 (t, J=, 3H), 3.98 (s, 3H), 4.21 (q, J=, 2H), 4.89 (s, 2H), 7.34 (dd, J=10.3 and 1.6 Hz, 1H), 7.40 (t, J=1.6 Hz, 1H), 9.88 (d, J=1.6 Hz, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.0, 57.6, 62.1, 70.3, 110.0, 111.8 (d, J=20.6 Hz), 133.1 (d, J=7.2 Hz), 141.8 (d, J=12.7 Hz), 154.5 (d, J=4.5 Hz), 156.0 (d, J=246 Hz), 169.7, 191.3. MS (ESI): m/z 256.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[NH:8][C:9](=[O:20])[C:10]3[N:15]([CH3:16])[N:14]=[C:13]([CH2:17][CH2:18][CH3:19])[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.O.[C:24]([OH:28])(=[O:27])[CH:25]=O>[Pd].CO>[CH3:16][N:15]1[C:10]2[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][CH2:25][C:24]([OH:28])=[O:27])=[CH:3][CH:4]=3)=[N:12][C:11]=2[C:13]([CH2:17][CH2:18][CH3:19])=[N:14]1
Reactant: O=CC(=O)O
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(N)cc3)nc12
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NCC(=O)O)cc3)nc12
Reaction time: 3 h

Procedure:
10% w/w Palladium on charcoal (87 mg) was added to a solution of 5-(4-aminobenzyl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7-one (870 mg, 0.00293 mol) and glyoxylic acid hydrate (260 mg, 0.0035 mol) in methanol (20 ml) and the mixture hydrogenated at room temperature at 50 p.s.i. for 3 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH2:24]([NH:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: CCCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-butylaminophenyl)-5-phenylbenzoxazole (409 mg, 1.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (219 mg, 1.14 mmol) the title compound was obtained (390 mg, 64%). 1H NMR (DMSO) δ 8.71(t, 1H), 8.65(dd, 1H), 8.36(d, 1H), 8.29(m, 2H), 8.08(d, 1H), 8.00(d, 2H), 7.93(dd, 1H), 7.73(m, 3H) 7.62(t, 1H), 7.27(d, 1H), 3.60(m, 2H), 1.97(q, 2H), 1.74(m, 2H), 1.22(t, 3H) MS 532 m/z (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.[H-].[Na+].[CH3:26]I.O>CN(C=O)C>[CH3:26][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:5]2=[N:4][N:3]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)[C:2](=[O:1])[C:6]2=[CH:7]1
Reactant: CI
Reactant: O=C(O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c(=O)n(-c3ccc(C(=O)O)cc3)nc-2c2ccccc21
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A suspension of 4-(3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.050 g, 0.16 mmol) in DMF (1 ml) was added in small portions to a suspension of NaH (55%) (0.017 g, 0.39 mmol) in DMF (0.5 ml) under N2. The reaction was stirred at room temperature. After 1 h MeI (0.053 g, 0.38 mmol) was added. After additional 24 h water was added and the solid material (mainly consisting of ester product) was removed by filtration. The filtrate was acidified with 2M HCl. The precipitate was collected, washed with water and dried to yield 4-(5-methyl-3-oxo-3,5-dihydro-pyrazolo[4,3-c]quinolin-2-yl)-benzoic acid (0.018 g). This material contained approx. 10% of ester product: 1H NMR (400 MHz, DMSO-d6) δ 8.89 (1H, s), 8.34 (2H, d), 8.29 (1H, d), 7.99 (2H, d), 7.85 (1H, d), 7.76 (1H, t), 7.62 (1H, t), 4.00 (3H, s); ESI MS m/z 320 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([O:20]C(C)(C)C)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([O:16][CH3:17])=[N:11][C:10]=1[C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1nc(C(=O)OC(C)(C)C)c(OCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C(=O)O)c(OCc2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of Compound 43c (1.1 g, 3.2 mmol) in MeOH (20 mL) and THF (20 mL) was added 7 N NaOH (4.0 mL, 28 mmol) and the solution stirred at 50° C. for 3 h. The reaction mixture was cooled in an ice bath then acidified by the addition of 1 N HCl (20 mL). The resulting precipitate was filtered, rinsed with water then dried under vacuum to give Compound 43a (790 mg, 89% yield) as a white solid. LCMS=1.41 min using analytical method (Q), 277.0 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 13.49 (br. s., 1H), 12.91 (br. s., 1H), 7.90-6.67 (m, 5H), 5.01 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[OH:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:9][C:10]1[C:18]2[N:17]=[C:16]([CH3:19])[NH:15][C:14]=2[CH:13]=[CH:12][C:11]=1[O:20][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2c(Cl)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(Cl)c(Oc3cc(Cl)ncn3)ccc2[nH]1

Procedure:
270 mg (1.81 mmol) 4,6-dichloropyrimidine, 330 mg (1.81 mmol) 4-chloro-5-hydroxy-2-methyl-1H-benzo[d]imidazole and 270 mg (1.95 mmol) potassium carbonate in 1.5 mL DMF were stirred for 2 h at RT. The reaction mixture was mixed with water and the precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>C(#N)C>[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A solution of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (7.10 g, 36.4 mmol, intermediate F) and DIEA (16 mL, 92 mmol) in 100 mL of acetonitrile was heated to 80° C. This solution was treated dropwise with a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (10.5 g, 37.0 mmol, intermediate J) in acetonitrile (80 mL) over a period of 4 hours. After the addition was completed, the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then allowed to cool to rt, and the volume was reduced by rotary evaporation to 80 mL. A satd. NH4Cl solution (100 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (2×100 mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography (750 g of silica gel) eluting with a gradient of 0% to 20% of solvent B in solvent A, where Solvent B=20% methanol/DCM and solvent A=DCM. Fractions containing the product were combined. Evaporation of the solvents gave 9.3 grams of the desired product with 97% purity by LC/MS analysis (conditions B). The product thus obtained (8.5 g) was slurried in acetone:hexane (1:5, 200 mL) and the solid product was isolated by filtration and air dried. Careful SFC analysis showed the presence of a 2.1% impurity in the product. Using a Cell4 0.46×25 cm 5 μm column and eluting with 45% methanol in CO2 at 3 mL/min, the desired product eluted at 3.800 minutes and the undesired impurity eluted at 4.848 minutes. The product was then further purified by SFC Chromatography using a Cell4 3×25 cm 5 μm column at 150 mL/min injecting 1.5 mL of a 80 mg/mL solution. Concentration of the active fractions provided 7.82 grams (20.4 mmol, 56%) of >99.7% pure example 1 as a white powder. LC/MS (Conditions B), RT=2.512 min, (M+H)+=383.3. 19F NMR δ −182.83. 1H NMR (400 MHz, chloroform-d) δ 7.20-7.08 (m, 6H), 6.98-6.78 (m, 2H), 5.68 (s, 1H), 4.77-4.54 (m, 1H), 4.53-4.34 (m, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.41-3.29 (m, 1H), 3.28-3.09 (m, 2H), 2.82 (d, J=10.8 Hz, 1H), 2.74-2.54 (m, 2H), 2.47 (td, J=9.9, 3.6 Hz, 1H), 2.34 (s, 3H), 2.19-1.94 (m, 2H), 1.92-1.80 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 172.4, 154.9, 137.5, 133.3, 133.0, 129.5, 128.7, 128.3, 115.5, 92.6, 90.8, 65.0, 54.4, 54.2, 48.7, 48.0, 47.8, 46.8, 43.7, 31.7, 31.6, 21.1, 19.6.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1>>[CH3:17][C:2]1[N:20]2[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]2=[N:18][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)C(C)O2
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc2nc(-c3ccc4c(c3)NC(=O)C(C)O4)c(C)n2c1
Yield: 72.8 %

Procedure:
6-(3,6-Dimethylimidazo[1,2-a]pyridin-2-yl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.8 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.4 g) and 2-amino-5-methylpyridine (2.6 g). mp. 232° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:12]=1[Cl:11]
Reactant: C#Cc1ccc(F)cc1F
Reactant: SCc1ccc(Cl)cc1Cl
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2F)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2Cl)c(F)c1

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 2,4-dichlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-2,4-dichlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:13][CH2:14][Cl:15])=[CH:6][C:5]=1[NH2:16].Cl.[CH:19](N)=[NH:20]>C(O)C>[Cl:15][CH2:14][CH2:13][O:12][C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:20][CH:19]=[N:16]2)=[CH:9][C:8]=1[O:10][CH3:11]
Reactant: COC(=O)c1cc(OC)c(OCCCl)cc1N
Reactant: N=CN
Agent: Cl
Solvent: CCO
Product: COc1cc2c(O)ncnc2cc1OCCCl
Temperature: 130 °C
Yield: 95.6 %

Procedure:
To a solution of 2-amino-4-(2-chloro-ethoxy)-5-methoxy-benzoic acid methyl ester (2.4 g, 9.24 mmol) in ethanol was added formamidine hydrochloride (2.97 g, 36.96 mmol). The mixture was heated at 130° C. in sealed tube for 8 h. The precipitate formed was filtered and washed with ethanol and dried to afford the pure compound 7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ol (2.25 g, 96%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.45 (s, 2H), 7.15 (s, 1H), 4.40 (t, 2H), 4.00 (t, 2H), 3.88 (s, 3H), LC-MS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH2:1][Cl:18])[N:3]=2)=[CH:9][CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Temperature: 25 °C

Procedure:
A solution of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then was stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(4-bromophenyl-4-(chloromethyl)-5-methyloxazole as a lime-green powder: Rf=0.39 in 20% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) 7.88–7.86 (m, 2H), 7.59–7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); 13C (125 MHz, CDCl3) 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7, 37.1, 11.5; IR (KBr) 2970, 1633, 1599, 1481, 1401, 1258, 1117, 1008 cm−1; UV (EtOH)max 281 nm (21349); HRMS (FAB) m/z calculated for C11H1079BrClNO: 285.9634, found 285.9641; Anal. Calculated for C11H9ClBrNO: C, 46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H 3.07; N, 4.81; Cl, 12.36; Br, 27.88.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OCC)C=1)[CH2:3]C(O)=O.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[CH2:20][C:21]([OH:23])=[O:22]>>[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[C:26]([O:33][CH3:34])[CH:25]=1)[CH2:20][C:21]([O:23][CH2:2][CH3:3])=[O:22]
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Reactant: CCOc1ccc(C(N)CC(=O)O)cc1OC
Product: CCOC(=O)CC(N)c1ccc(OCC)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 26 except that 3-amino-3-(3-ethoxy-4-methoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-ethoxy-phenyl)propionic acid. MS (m/z): 268 [M+1]+.
Reaction SMILES: [ClH:1].Cl.[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH:20]([CH3:36])[C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=2[Cl:33])[CH:24]=1)=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:33].[ClH:1].[N+:3]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:20]([C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([O:34][CH3:35])[C:29]=4[Cl:33])[CH:24]=3)=[O:22])[CH3:36])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: O=[N+]([O-])c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccc([N+](=O)[O-])cc4)CC3)ccc2c1Cl
Yield: 108.2 %

Procedure:
A mixture of N-(4-nitrobenzyl)piperazine dihydrochloride (2.94 g, 10 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (3.93 g, 12 mmol) and K2CO3 (4.83 g, 35 mmol) in 50 ml of DMF was treated according to general preparation 2 to give 3.51 g of compound (IV-32), yield 65%. M+ 467.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][O:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.Cl.[CH3:16][NH:17][O:18][CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH3:19][O:18][N:17]([CH3:16])[C:10](=[O:12])[CH2:9][O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=1
Reactant: COc1ccc(COCC(=O)O)cc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COCC(=O)N(C)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of [(4-methoxybenzyl)oxy]acetic acid (Bioorganic and Medicinal Chemistry Letters, 2001, pp. 2837-2841) (6.86 g, 0.0350 mol) and N,O-dimethylhydroxylamine hydrochloride (3.41 g, 0.0350 mol) in DCM (100 mL) was added benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (17 g, 0.038 mol) followed by TEA (9.7 mL, 0.070 mol). The resulting mixture was stirred overnight at room temperature. The solution was then washed with water, 0.5 M HCl, saturated NaHCO3, and brine, then was dried over sodium sulfate, filtered and concentrated in vacuo. Flash column chromatography (ether/hexanes) afforded the desired product (5.75 g, 69%).
Reaction SMILES: [CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[CH2:25][CH2:26][O:27][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCN1CCCCC1CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCCCCCCCN1CCCCC1CCOS(=O)(=O)c1ccc(C)cc1

Procedure:
1,4-Dioxane solution of 2-(1-octadecyl-2-piperidyl)ethan-1-ol and p-toluenesulfonyl chloride is added to sodium hydroxide solution and then the mixture is reacted at room temperature to obtain 1-octadecyl-2-[2-(tosyloxy)ethyl]piperidine.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[C:35]([O:39][C:40]([NH:42][S:43]([C:46]1[CH:54]=[CH:53][CH:52]=[CH:51][C:47]=1[C:48](O)=[O:49])(=[O:45])=[O:44])=[O:41])([CH3:38])([CH3:37])[CH3:36].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:48]([C:47]5[CH:51]=[CH:52][CH:53]=[CH:54][C:46]=5[S:43]([NH:42][C:40](=[O:41])[O:39][C:35]([CH3:37])([CH3:36])[CH3:38])(=[O:44])=[O:45])=[O:49])[CH2:23][CH2:24]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1ccccc1C(=O)O
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (238 mg, 0.47 mmol, 1 eq.) in dimethylformamide (14 mL) was added 2-{[(tert-butoxycarbonyl)amino]sulfonyl}benzoic acid 1b (140 mg, 0.47 mmol, 1 eq.) and N,N-diisopropylethyl amine (0.3 mL, 1.41 mmol, 3 eq.). After stirring at RT for several minutes, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (179 mg, 1.41 mmol, 1 eq.) was added and the reaction was stirred for 2 h. The mixture was partitioned between dichloromethane and water. The organic layer was dried and concentrated to provide crude tert-butyl {2-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]phenyl}sulfonylcarbamate 1c. The crude product was used without further purification.