Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].COCCOCCOC.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCCCCCCCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 64.0 g (0.236 mole) of octadecanol and 500 ml of bis(2-methoxyethyl)ether is stirred at room temperature under nitrogen after which 9.45 g (0.393 mole) of sodium hydride is added. The mixture is refluxed about 22 hours, allowed to cool and poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, and filtered. The solvent is evaporated off replacing the ether with hexane. Upon cooling to room temperature a solid forms which is recrystallized from methanol to give 5-octadecyloxy-2-furoic acid, M.P. 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:30])[C:26]([NH:28][NH2:29])=[O:27])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:36](N2C=NC=C2)=[O:37])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25]([C:26]3[O:27][C:36](=[O:37])[NH:29][N:28]=3)=[O:30])[CH2:16][C@@H:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (45)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate, intermediate 26, (542 mg, 1.25 mmol) in THF (16 mL) is added CDI (244 mg, 1.50 mmol) at room temperature. After stirring for 18 hour at room temperature, the reaction is quenched with H2O and 1M HCl and diluted in EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) and by Chiral-HPLC (OJ-H 21×250 mm, EtOH(0.1% TFA)/Heptane=30/70) to give (2R,4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-2-methyl-4-(5-oxo-4,5-dihydro-1,3,4-oxadiazole-2-carboxamido)pentanoate (333 mg). HPLC retention time=1.74 minutes (condition A); MS 458.2 (M+1); 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=7.1 Hz, 3 H) 1.12 (t, J=7.1 Hz, 3 H) 1.58-1.74 (m, 1 H) 1.76-1.91 (m, 1 H) 2.45-2.50 (m, 1 H) 2.77 (dd, J=13.7, 7.9 Hz, 1 H) 2.86 (dd, J=13.7, 7.9 Hz, 1 H) 4.00 (q, J=7.1 Hz, 2 H) 4.06-4.22 (m, 1 H) 7.28 (d, J=8.1 Hz, 2 H) 7.37-7.42 (m, 1 H) 7.47 (t, J=7.8 Hz, 1 H) 7.58-7.66 (m, 3 H) 7.67-7.73 (m, 1 H) 8.86 (d, J=8.8 Hz, 1 H) 12.95 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.[Li]CCCC.[I:30]I.[Cl-].[NH4+]>C(OCC)C.C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([O:15][CH3:16])[C:10]=1[I:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(=O)OC(C)(C)C)ccn1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1nccc(NC(=O)OC(C)(C)C)c1I
Temperature: -78 °C
Reaction time: 3 h
Yield: 23.1 %

Procedure:
A solution of 4-[(tert-butoxycarbonyl)amino]-2-methoxypyridine (1.8 g, 8.03 mmol, 1.0 equiv) in 100 mL of anhydrous diethyl ether was treated with 2.79 mL of N,N,N′,N′-tetramethylethylenediamine (18.5 mmol, 2.3 equiv) under an inert atmosphere. The resulting solution was cooled to −78° C., treated with n-BuLi (2.5 M, 7.2 mL, 18.0 mmol, 2.24 equiv) and warmed to −7° C. The reaction was stirred at −7° C. to 0° C. for 3 hours, cooled to −78° C. and treated with a solution of iodine (3.05 g, 12 mmol) in 30 mL of anhydrous THF. The resulting mixture was stirred to room temperature for 16 hours. 200 mL of saturated ammonium chloride solution and 100 mL of diethyl ether were added. The phases were separated and the organic layer was washed with 100 mL of sodium thiosulfate (10% aqueous solution), dried over sodium sulfate, decanted, and concentrated in vacuo. Chromatography on SiO2 (100% dichloromethane to 5% methanol in dichloromethane, gradient) provided the title product (650 mg, 23% yield) as a white wax.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([C:27]2[CH:36]=[CH:35][C:30]([O:31][CH2:32][CH2:33]O)=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:30]2[CH:35]=[CH:36][C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][CH:29]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc(-c2ccccc2)cc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 29.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(4-phenylphenoxy)ethanol (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4:1) and the resulting solids were crystallized from dichloromethane-diethyl ether to provide 0.45 g of 4-[[2-[4-(1,1'-biphenyl)oxy]ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester as an 0.25 molar hydrate, mp 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[C:28]([CH3:30])[C:27]([C:31](O)=[O:32])=[N:26]2)=[CH:21][CH:20]=1>>[C:9]([NH:8][C:6]1[CH:7]=[C:2]([NH:1][C:31]([C:27]2[C:28]([CH3:30])=[CH:29][N:25]([C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)[N:26]=2)=[O:32])[CH:3]=[CH:4][C:5]=1[Cl:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cn(-c2ccc(F)cc2)nc1C(=O)O
Reactant: Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1
Product: Cc1cn(-c2ccc(F)cc2)nc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1

Procedure:
N-(5-amino-2-chlorophenyl)benzamide (0.24 mmol) was used in general procedure 2 with 1-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.30 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-1-(4-fluorophenyl)-4-methyl-1H-pyrazole-3-carboxamide. MS (Q1) 449.1 (M)+
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C[O:26][C@@H:27]2[C@@:31]3([CH2:38][O:39][C@H:28]2[C@:29]([SiH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([N:40]2[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]2=[O:42])[O:30]3)[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])C2C(=CC=CC=2)C=CC=1>C(Cl)Cl.O>[C:34]([O:33][CH2:32][C@@:31]12[CH2:38][O:39][C@@H:28]([C@:29]([SiH:48]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([N:40]3[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]3=[O:42])[O:30]1)[C@@H:27]2[OH:26])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1OCc1cccc3ccccc13)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1O)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.5 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (15.9 g, 70.0 mmol) was added to a mixture of compound 11 (19.7 g, 31.1 mmol) in CH2Cl2 (200 mL) and H2O (40 mL). After 7 hours of vigorous stirring at room temperature, the mixture was poured into CH2Cl2 (1 L). The resulting solution was washed with 2% (w/v) aqueous sodium bisulfite, followed by saturated aqueous NaHCO3, then dried over anhydrous Na2SO4, filtered, then evaporated to a light-brown foam. Purification by silica gel chromatography (2.5 vol. % methanol in CH2Cl2) yielded 15.0 g (97%) of 12 as an off-white foam.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[C:14]1([C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:9]3[C:10](=[O:12])[CH2:11][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:8]3=[O:13])=[O:25])=[CH:27][CH:28]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C1CN(c2ccccc2)C(=O)N1C(=O)c1ccc(-c2ccccc2)cc1
Yield: 9.4 %

Procedure:
In a similar manner to Example 8, 530 mg (3.00 mmol) of 1-phenyl-imidazolidin-2,4-dione were reacted with 650 mg (3.00 mmol) of 4-phenylbenzoyl chloride. After completion of the reaction, pyridine was distilled off under reduced pressure, and the resultant residue was subjected to extraction with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and with saturated saline. The thus-washed organic layer was dried over anhydrous magnesium sulfate, and the solvent was then distilled off. The resultant residue was purified by column chromatography on silica gel (developing solvent: n-hexane/ethyl acetate) and subjected to crystallization from n-hexane/ethyl acetate to obtain 100 mg (yield: 9.9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=[O:6].[CH3:14][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH3:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
To a stirred solution at −10° C. of 3-chloro-5-(trifluoromethyl)benzaldehyde (Reference Example 31, 1.15 g, 5.51 mmol) in THF (20.0 mL) was added dropwise methyl magnesium bromide (2.30 mL, 3.0 M in ethyl ether, 6.90 mmol). After the addition was complete, the reaction mixture was stirred for an additional 1.5 h, then the reaction was quenched with saturated ammonium hydrochloride (30.0 mL), and the mixture was warmed to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure to provide 1-(3-chloro-5-(trifluoromethyl)phenyl)ethanol (1.17 g, 94%) as a pale yellow oil, which was used without further purification or characterization.
Reaction SMILES: Cl.C[O:3][C:4](=[O:31])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:27](=[CH:28][CH:29]=1)[O:26][C:12]1([CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:30]>CC(O)=O>[O:30]=[C:10]1[C:9]2[C:27](=[CH:28][CH:29]=[C:7](/[CH:6]=[CH:5]/[C:4]([OH:31])=[O:3])[CH:8]=2)[O:26][C:12]2([CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCNCC1)O2
Temperature: 85 °C
Reaction time: 3 h
Yield: 106 %

Procedure:
20% aqueous HCl (10 ml, 55 mmol) was added to a suspension of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (Intermediate 3, Step B, 954 mg, 2.3 mmol) in glacial AcOH (10 ml). The mixture was stirred at 85° C. for 3 h and then evaporated under vacuum to give (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (735 mg) as a white solid (hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=[O:11]>[OH-].[Na+].O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1cccc(Oc2cccc(OC)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cccc(Oc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 3-(3-methoxyphenoxy)benzoate (0.090 g; 0.331 mmol) was dissolved in a mixture of NaOH 1M (2 mL) and dioxane (2 mL) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue washed with dichloromethane, acidified to pH 2 with a 6N solution of hydrochloric acid in water, and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford quantitatively the title compound which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@H:5](O)[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:44]([OH:47])(=[S:46])[CH3:45]>O1CCCC1.ClCCl>[CH3:1][N:2]1[CH2:6][C@@H:5]([S:46][C:44](=[O:47])[CH3:45])[CH2:4][C@H:3]1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N(C)C)N(C)C1
Reaction time: 0.5 h

Procedure:
(2S,4R)-1-Methyl-2-dimethylaminocarbonyl-4-hydroxypyrrolidine (970 mg) was dissolved in dry tetrahydrofuran (11.1 ml), and triphenylphosphine (2.66 g) was added thereto. To the resultant mixture, diethyl azodicarboxylate (1.60 ml) was added under nitrogen steam while ice-cooling, and the mixture was stirred for 30 minutes. Thioacetic acid (1.45 ml) was added to the mixture under ice-cooling, and stirring was continued for 40 minutes under ice-cooling, followed by allowing to stand overnight. The reaction mixture was diluted with dichloromethane, washed with aqueous potassium carbonate solution and dried over magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to give (2S,4S)-1-methyl-2-dimethylaminocarbonyl-4-acetylthiopyrrolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH2:8][OH:9]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]2[NH:12][C:11]([CH2:13][CH2:14][CH2:15][CH3:16])=[N:10][C:5]2=[N:6][C:7]=1[CH:8]=[O:9]
Reactant: CCCCc1nc2nc(CO)c(Br)cc2[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCCCc1nc2nc(C=O)c(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
1.04 g (3.66 mmole) of the compound obtained in step 6 was dissolved in 5 ml of CH2Cl2 and thereto was added 3.2 g (36.6 mmole) of activated MnO2. The reaction solution was stirred for 16 hours at room temperature and filtered through Cellite. The resultant was concentrated under reduced pressure to obtain 0.57 g of the title compound (yield 55%).
Reaction SMILES: [Cl-].[CH3:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH3:9])[N:4]1[CH2:10][CH2:11][NH3+:12].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[C:17](OC)=[O:18]>C1COCC1>[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[F:24])[C:17]([NH:12][CH2:11][CH2:10][N:4]1[C@H:5]([CH3:9])[CH2:6][CH2:7][CH2:8][C@@H:3]1[CH3:2])=[O:18]
Reactant: COC(=O)c1ccc(F)c(N)c1
Reactant: C[C@@H]1CCC[C@H](C)N1CC[NH3+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(N)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture comprising 2-(2,6-cis-dimethylpiperidin-1-yl)ethanaminium chloride (4 g, 20.75 mmol) and methyl 3-amino-4-fluorobenzoate (3.51 g, 20.75 mmol) in THF (50 ml) was treated with TBD (2.89 g, 20.75 mmol) and stirred at 80° C. for 16 hrs. A further portion of methyl 3-amino-4-fluoro benzoate (1 g) and TBD (0.5 g) were added and heating continued for 24 hrs. The resulting mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted once with ethyl acetate and once with chloroform. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Purification of the residue by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9]C2SC=CC=2)=[N:6][CH:7]=1.[CH3:32][CH:33]([C:35]1[O:39]C(N)=[N:37][CH:36]=1)[CH3:34]>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][P:25]([CH3:29])(=[O:28])[CH2:26][CH2:27]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][C:9]2[O:39][C:35]([CH:33]([CH3:34])[CH3:32])=[CH:36][N:37]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Reactant: CC(C)c1cnc(N)o1
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Nc2ncc(C(C)C)o2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 5-(propan-2-yl)-1,3-oxazol-2-amine.
Reaction SMILES: C([O:6][CH2:7][CH2:8][CH2:9][S:10]([O-:13])(=[O:12])=[O:11])(=O)C(C)=C.[C:14]1([S+:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+].Cl.C(C(C)=O)C(C)C>CO>[OH:6][CH2:7][CH2:8][CH2:9][S:10]([O-:13])(=[O:12])=[O:11].[C:27]1([S+:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=C(C)C(=O)OCCCS(=O)(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)CC(C)C
Product: O=S(=O)([O-])CCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 100 g of methylene chloride were added 2.5 g (10 mmol) of a potassium salt of 3-sulfopropyl methacrylate and 23 g (10 mmol) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1. The mixture was stirred at room temperature for 30 minutes. The organic layer was taken out and washed with water. It was combined with ethanol and concentrated in vacuum while azeotroping off the residual water. There was obtained 3.3 g of triphenylsulfonium 3-methacryloyloxypropanesulfonate. To 3.3 g of triphenylsulfonium 3-methacryloyloxypropanesulfonate were added 100 mg (0.6 mmol) of 28 wt % sodium methoxide in methanol and 15 g of methanol. The mixture was stirred at room temperature for 3 days. Then 70 mg of 35% aqueous hydrochloric acid was added to quench the reaction. The reaction solution was combined with methyl isobutyl ketone and concentrated in vacuum while distilling off the residual water. Diisopropyl ether was added to the residue for recrystallization. The crystals were collected and dried, obtaining the target compound, triphenylsulfonium 3-hydroxypropanesulfonate. White crystals, 2.1 g, yield 52%. The compound, designated PAG intermediate 2, has the following structure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1.[CH3:32][O:33][CH2:34][C:35]#[CH:36].C(NC(C)C)(C)C>[Cu]I.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:36]#[C:35][CH2:34][O:33][CH3:32])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH2:28][CH2:29][CH2:30][Cl:31])=[CH:20][C:21]=2[O:23][CH:24]([CH3:26])[CH3:25])[N:16]=[CH:15][N:14]=1
Reactant: C#CCOC
Reactant: CC(C)Oc1cc(OCCCCl)cc2ncnc(Nc3c(Cl)cc(I)c4c3OCO4)c12
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)cc(OC(C)C)c23)c2c1OCO2
Temperature: -10 °C

Procedure:
A mixture N-(5-chloro-7-iodo-1,3-benzodioxol-4yl)-7-(3-chloropropoxy)-5-isopropoxyquinazolin-4-amine (1.313 g, 1:1 wt.:wt. mixture with triphenylphosphine), 3-methoxy-prop-1-yne (0.19 ml), palladium(II) bis-triphenylphosphine dichloride (0.080 g) and copper (I) iodide (0.022 g) was taken up into ethyl acetate (15 ml) and cooled to −10° C. This was set to stir rapidly and then diisopropylamine (0.32 ml) was added and the reaction was stirred cold for 45 minutes before being warmed to room temperature and left to stir for a further 90 minutes. The reaction mixture was then filtered through Celite under suction (washing the Celite with a further portion of ethyl acetate) then the combined filtrate solutions were evaporated under reduced pressure to leave a brown gum. The gum was then purified by column chromatography on silica using diethyl ether as eluent. There was thus obtained the title compound (as a 1:1.3 wt.:wt. mixture with triphenylphosphine) (1.056 g) as a yellow solid; NMR Spectrum: (CDCl3) 1.53 (d, 6H), 2.30 (quin, 2H), 3.45 (s, 3H), 3.76 (t, 2H), 4.25 (t, 2H), 4.35 (s, 2H), 4.83 (sept, 1H), 6.10 (s, 2H), 6.49 (d, 1H), 6.85 (d, 1H), 7.06 (s, 1H), 8.52 (s, 1H), 9.42 (s, 1H)—triphenylphosphine 7.46 (m, 6H), 7.54 (m, 3H), 7.67 (m, 6H);
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)C#N)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CS(C)=[O:26]>>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[O:26])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(C)=O
Reactant: N#CC(c1cccs1)C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1cccs1)C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 35 %

Procedure:
To a stirred mixture of 29.6 parts of 1-(phenylmethyl)-α-(2-thienyl)-4-piperidineacetonitrile in 100 parts of dimethyl sulfoxide are added portionwise 4 parts of sodium hydride dispersion 60%. Upon completion, stirring is continued overnight. The reaction mixture is poured onto water. The precipitated product is sucked off and extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane, yielding 10 parts (35%) of [1-(phenylmethyl)-4-piperidinyl] (2-thienyl) methanone; mp. 100.5° C.
Reaction SMILES: CCCCCC.[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(OCC)(=[O:27])C>>[Cl:7][C:8]1[CH:9]=[C:10]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]2=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(C)=O
Reactant: COc1ccc(-n2ccc3ccccc32)cc1Cl
Solvent: CCCCCC
Product: COc1ccc(N2C(=O)Cc3ccccc32)cc1Cl

Procedure:
Using 3:2 hexane:ethyl acetate as eluant on chromatography, the procedure of the preceding preparation was used to convert 1-(3-chloro-4-methoxyphenyl)indole (0.93 g) to present title product, 0.71 g, m.p. 165°-167°.