Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:13]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=[C:15]3[N:24]([CH3:28])[N:25]=[C:26]([CH3:27])[C:14]=23)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)c2c(C(=O)O)cnc3c2c(C)nn3C)cc1
Yield: 77.6 %

Procedure:
A mixture of 1.34 g (2.7 mmol) of ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-_ylmethylamino]-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-carboxylate, 2.97 ml of 1N potassium hydroxide in 7.8 ml of ethanol and 4.83 ml of water was refluxed for 20 hr. Another 0.54 ml of 1N potassium hydroxide was added and the mixture refluxed 4 hrs. The solvent was removed under vacuum and toluene added and removed under vacuum. The residue was dissolved in water (20 ml) and extracted with ethyl acetate. The aqueous layer was acidified with 2 N citric acid and the precipitated solid filtered off and washed with water. The solid was dried under vacuum to give 0.98 g of solid, mp 256-258° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]C(=O)/C=C\C(O)=O)=[O:10])[CH:6]=[CH:5][N:4]=1.O=P(Cl)(Cl)Cl.[NH2:24][NH:25][C:26]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1)=[N:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34]>C1(C)C=CC=CC=1>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N:27]1[C:6](/[CH:7]=[CH:8]/[C:3]2[O:10][C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=3)=[N:11][N:4]=2)=[N:24][N:25]=[C:26]1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[CH:37][N:36]=1
Reactant: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Reactant: CCOc1ccc(C(=Nc2ccccc2Cl)NN)nc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1ccc(-c2nnc(/C=C/c3nnc(-c4ccnc(OC)c4)o3)n2-c2ccccc2Cl)nc1

Procedure:
To a suspension of (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 (0.30 g, mmol) in 20 mL of PhMe was added 0.5 mL of POCl3. The mixture was stirred at reflux for 2 h. After removal of solvent, the residue was dissolved in 20 mL of dichloromethane and added to 240 mg (0.68 mmol) of N-amino-N′-(2-chlorophenyl)-5-ethoxy-pyridine-2-carboxamidine 5. The mixture was stirred at ambient temperature for 2 h. After removal of solvent, the residue was suspended in 20 mL of PhMe and refluxed for 3 h. After removal of solvent, the residue was purified by column (0-5% of methanol in dichloromethane) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-ethoxypyridine as a solid. Yield: 20 mg, 3.5%.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[K+]>[CH2:6]([O:13][CH2:1][CH:3]1[CH2:4][O:5]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClCC1CO1
Reactant: OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: c1ccc(COCC2CO2)cc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 50% w/w aqueous potassium hydroxide (30 mL), epichlorohydrin (157 mmol, 20 mL) and tetrabutylammonium bromide (2.35 mmol, 0.75 g) was vigorously stirred at room temperature and cooled in an ice bath. Benzyl alcohol (96.0 mmol, 10 ml) was added dropwise, while maintaining the reaction temperature at about 10° C. by cooling the reaction mixture in an ice bath. The reaction mixture was then allowed to stir at room temperature overnight after which it was poured onto ice/water, and the aqueous phase extracted with diethyl ether. The organic phases were combined and washed with brine to neutrality and dried (Na2SO4). The solution was concentrated under reduced pressure. The residue was purified by flash chromatography (silica, 2-10% ethyl acetate/heptane) to give 14.8 g (94%) of 2-benzyloxymethyl-oxirane.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26]([CH:35]=O)=[CH:25]2)=[CH:19][CH:18]=1.C(OP([CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])(OCC)=O)C.O>CN(C)C=O>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[N:22]=[CH:21][C:20]([CH2:23][N:24]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:26](/[CH:35]=[CH:45]/[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:25]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, oily, 190 mg) was added to a solution of 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolecarbaldehyde (1.05 g) and ethyl diethylphosphonoacetate (1.05 g) in N,N-dimethylformamide (50 ml) at 0° C., and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration to obtain ethyl(E)-3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propenoate. The crystals were dissolved in ethanol (80 ml), and hydrogenated on 5% palladium-carbon (800 mg) at room temperature under a normal pressure. The catalyst was filtered, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1.05 g, yield: 86%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume 5 ratio).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)CC2
Yield: 91.2 %

Procedure:
6-Nitroindan-1-one (18.1 g, 102 mmol) was dissolved in ethanol (400 ml) and reduced using Pd (5%) on carbon (2.0 g) and 35 psi hydrogen pressure on a Parr apparatus. Filtration on celite followed by evaporation gave 6-aminoindan-1-one (13.7 g, 93 mmol). NMR (DMSO) 7.2 (d, J=7.7Hz, 1H), 6.9 (dd, Jab=7.7Hz, J ax=2.3 Hz, 1H), 6.75 (d, J=2.3Hz, 1H), 5.3 (br s, 2H), 2.9 (t, J=5.6 Hz, 2H), 2.55 (t, J=5.6 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14]C)[CH:11]=[C:10]2[C:5]=1[C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=1)[CH:8]=[N:9]2)[CH3:2].C([S-])C.[Na+].Cl>CN(C)C=O.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:24])[N:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH:8]=[N:9]2)[CH3:2]
Reactant: CCOc1cc(OC)cc2ncn(-c3ccc(OC)cc3)c(=O)c12
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(O)cc2ncn(-c3ccc(O)cc3)c(=O)c12
Temperature: 120 °C
Reaction time: 7 h
Yield: 23.3 %

Procedure:
To a solution of 5-ethoxy-7-methoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinone (0.0080 g, 0.0245 mmol), as prepared in Example 41, in dimethylformamide (0.25 mL), was added sodium ethanethiolate (0.0047 g, 0.0563 mmol). The resulting suspension was warmed to 120° C. to form a solution. After each hour (for 7 hours) additional sodium ethanethiolate (0.0047, 0.0563 mmol) was added. After 7 hrs, the cloudy orange reaction solution was cooled to room temperature and diluted with water (0.75 mL). The resulting yellow solution was acidified with 1.0N HCl to pH 3 wherein the reaction solution became cloudy. Extraction was performed with EtOAc (3×) and dichloromethane (3×). The combined organic layers were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Column chromatography (5% MeOH in CH2Cl2) gave 0.0017 g (23%) of 5-ethoxy-7-hydroxy-3-(4-hydroxyphenyl) quinazoline-4-one, as a white solid.
Reaction SMILES: CC1(C)CC(C)(C)C2C(=C(C)C=C([C:14]([OH:16])=[O:15])C=2)O1.[CH3:19][C:20]1([CH3:37])[CH2:29][CH2:28][C:27]([CH3:31])([CH3:30])[C:26]2[CH:25]=[C:24](Br)[C:23]([O:33][CH2:34][O:35][CH3:36])=[CH:22][C:21]1=2.[Li]C(C)(C)C>>[CH3:36][O:35][CH2:34][O:33][C:23]1[C:24]([C:14]([OH:16])=[O:15])=[CH:25][C:26]2[C:27]([CH3:31])([CH3:30])[CH2:28][CH2:29][C:20]([CH3:37])([CH3:19])[C:21]=2[CH:22]=1
Reactant: COCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Reactant: Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Agent: [Li]C(C)(C)C
Product: COCOc1cc2c(cc1C(=O)O)C(C)(C)CCC2(C)C

Procedure:
Using the same procedure as for the synthesis of 2,2,4,4,8-pentamethyl-6-chromanoic acid (Compound A1) but using 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-methoxymethoxy-2-bromonaphthalene (Compound J, 722 mg, 2.21 mmol) and 2.86 ml of t-BuLi (4.87 mmol, 1.7M solution in hexane), the title compound was obtained as a white solid (143 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:13])[C:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[OH:13][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[C:10]([O:12][CH2:8][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[O:11]
Reactant: ClCCOCCCl
Reactant: Nc1ccc(CC(O)C(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@H](O)Cc1ccc(N2CCOCC2)cc1
Temperature: 25 °C

Procedure:
The suspended solution of benzyl R)-3-(4-aminophenyl)-2-hydroxypropionate (0.27 g), bis(2-chloroethyl)ether (0.12 ml), potassium carbonate (0.28 g), and sodium iodide (0.075 g) in dimethylformamide (1 ml) were heated at 70°-90° C. for 7 hours. After cooling it down to room temperature, water (50 ml) was added and extracted with ether (25 ml×3). After the ether layer was washed with saturated brine, it was dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, the resultant crude product was purified by silica gel column chromatography, and eluted with mixture of hexane, ethyl acetate and ethanol (60:35:5, v/v). The fractions containing the desired product were combined and evaporated in vacuo to obtain benzyl (R)-2-hydroxy-3-(4-morpholinophenyl)propionate (0.14 g)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[F:18][C:19]([F:57])([F:56])[C:20]1[CH:21]=[C:22]([CH2:30][O:31][C@@H:32]2[CH2:38][CH2:37][C@@H:36]3[N:39]([CH2:40][CH:41]=[CH2:42])[C@@:33]2([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:34][C@H:35]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>C1COCC1>[F:56][C:19]([F:18])([F:57])[C:20]1[CH:21]=[C:22]([CH2:30][O:31][CH:32]2[CH2:38][CH2:37][CH:36]3[N:39]([CH2:40][CH:41]=[CH2:42])[C:33]2([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:34][CH:35]3[C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCN1C2CCC(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C1(c1ccccc1)CC2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of potassium bis(trimethylsilyl)amide in toluene (0.5M, 1.5 ml, 0.75 mmol) was added to a stirred solution of (1R*,2R*,5S*,6R*)-2-{[3,5-bis(trifluoromethyl)-phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-(prop-2-enyl)-8-azabicyclo[3.2.1]octane (Example 80; 362 mg, 0.635 mmol) in THF (5 ml) at +5° C. The mixture was stirred for 15 minutes and quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The organic extracts was washed with water, dried (Na2SO4) and concentrated to give the title compound as a 4.6:1 mixture diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8].CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([OH:47])[CH:45]=3)[N:40]=[CH:39][N:38]=2)=[N:32]1>O>[Cl:1][C:2]1[C:3]([O:47][C:44]2[CH:45]=[C:46]3[C:41](=[CH:42][CH:43]=2)[N:40]=[CH:39][N:38]=[C:37]3[NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([N:9]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:10])=[O:8]
Reactant: CN(C)CCN(C)C(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)C(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylnicotinamide (126 mg, 0.46 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred overnight under a nitrogen atmosphere at 130° C. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate to chloroform:methanol=1:4 to 100:2) to obtain the entitled compound (25 mg, yield: 25%) as a pale yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ncc2c(cc(-c3cnccn3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3cnccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyrazin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.10 mmol), β-alanine (735 mg, 8.25 mmol) and NaOMe solution (12.4 mL, 6.19 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 28 mg of the title compound as a light yellow solid. MS: (+) m/z 446.27 (M+1).
Reaction SMILES: N[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[O:28][CH:29]=2)[N:3]=1.N(OCCC(C)C)=O.[Cl-:45].[NH4+]>C(#N)C.[Cu](Cl)Cl>[Cl:45][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[C:12]([F:20])[CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:24][C:25]2[N:26]=[C:27]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[O:28][CH:29]=2)[N:3]=1
Reactant: [Cl-]
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Agent: [NH4+]
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.287 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-4-[3-fluoro-4-(2-hydroxyethoxy)phenyl]pyridine-3,5-dicarbonitrile (Example 20) are initially charged in 20 ml of acetonitrile, 258 μl (1.724 mmol) of isoamyl nitrite and 232 mg (1.724 mmol) of copper(II) chloride are added and the mixture is stirred at room temperature overnight. The reaction mixture is then added to saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5). This gives 25 mg (16% of theory) of the target compound.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[K+].[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+]>O>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([I:22])[CH:11]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(Br)cc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: O
Product: COC(=O)c1ccc(Br)cc1I
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 82.7 %

Procedure:
To methyl 2-amino-4-bromobenzoate (5.75 g) was added cooled 20% sulfuric acid (75 mL), sodium nitrite (2.07 g) was added by small portions under ice-cooling, and the mixture was stirred at the same temperature for 40 min. To this reaction mixture was added dropwise a solution of potassium iodide (8.3 g) in water (25 mL) under cooling to 5° C., 20% sulfuric acid (30 mL) was added, and the mixture was stirred at 5° C. for 2 hr. This reaction mixture was neutralized with 4N aqueous sodium hydroxide solution under ice-cooling, 10% aqueous sodium sulfite solution (45 mL) and sodium chloride were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium sulfite solution added saturated brine and saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (7.05 g).
Reaction SMILES: [C:1](Cl)(=[O:28])[O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/1=[N:14]\[C:15](=[O:27])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1F.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.CO>[N:30]1([C:1]([O:2][CH2:3][CH2:4][N:5]2[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[S:7]/[C:6]/2=[N:14]\[C:15](=[O:27])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[N:30]2[CH2:33][CH2:32][CH2:31]2)=[O:28])[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: CC(C)(C)c1cn(CCOC(=O)Cl)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cn(CCOC(=O)N2CCC2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2N2CCC2)s1
Reaction time: 2 h
Yield: 19.3 %

Procedure:
To a solution of Example 61B (174 mg, 0.384 mmol) in CH2Cl2 (1.4 mL) was added azetidine (110 mg, 1.920 mmol) in methanol (0.5 mL) and the mixture was stirred for 2 hr. The reaction mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10-100% acetonitrile (A) and 10 mM ammonium acetate in water (B), at a flow rate of 2.0 mL/min (0-0.1 min 10% A, 0.1-2.6 min 10-100% A, 2.6-2.9 min 100% A, 2.9-3.0 min 100-10% A. 0.5 min post-run delay) to obtain the title compound (38 mg, 0.074 mmol, 19.38%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (m, 9H) 1.99-2.12 (m, 2H) 2.18-2.29 (m, 2H) 3.78 (t, J=7.29 Hz, 4H) 3.87 (t, J=7.46 Hz, 4H) 4.35 (dd, J=14.24, 4.75 Hz, 4H) 6.57 (d, J=8.82 Hz, 1H) 7.27 (s, 1H) 7.51 (dd, J=8.65, 1.86 Hz, 1H) 7.87 (d, J=1.70 Hz, 1H); MS (DCI) m/z 511 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32]([S:35]([CH2:38]C5C=CC=CC=5)(=[O:37])=[O:36])[CH2:31][CH2:30]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1>C1COCC1>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
Methanesulfonyl chloride (0.009 mL, 0.12 mmol) and diisopropylethylamine (0.026 mL, 0.15 mmol) were added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) in anhydrous THF (3 mL). The reaction mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was dissolved in 1 mL DMSO. The DMSO solution was filtered and injected onto preparative HPLC. HPLC purification eluting with acetonitrile:water gave 0.012 g (28%) of the title compound as a yellow solid. MS (ESP+) m/z 427.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.65 (m, 1H), 7.83 (m, 1H), 7.56 (m, 1H), 7.45 (m. 1H), 7.03 (dd, 1H, J=1.8 Hz, 8.1 Hz), 6.97 (d, 1H, J=1.8 Hz), 6.88 (d, 1H, d=8.1 Hz), 6.05 (s, 2H), 3.91 (m, 2H), 3.47 (m, 1H), 2.89 (m, 2H), 2.84 (s, 3H), 2.22 (m, 2H), 2.11 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4](Br)[N:3]=1.[H-].[Na+].[CH3:36][O:37][CH2:38][CH2:39][OH:40]>C1COCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:19]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([O:40][CH2:39][CH2:38][O:37][CH3:36])[N:3]=1
Reactant: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(OCCOC)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of ethyl (2-amino-6-bromo-3-nitropyridin-4-yl)(4-((diethoxyphosphoryl)methyl)benzyl)carbamate (1 equiv.) in THF (0.30 M) was added sodium hydride (5 equiv.) in a solution of 2-methoxyethanol (0.50 M). The reaction mixture was allowed to stir at room temperature for 2 h. At this point the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (68%) as a solid.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1([C:19]([O:21]CC)=[O:20])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C>[CH2:1]([S:8][CH2:9][C:10]1([C:19]([OH:21])=[O:20])[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(CSCc2ccccc2)Cc2ccccc2O1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(CSCc2ccccc2)Cc2ccccc2O1
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A solution of ethyl 2-benzylthiomethyl-2,3-dihydrobenzofuran-2-carboxylate (2.70 g, 8.53 mmol) in ethanol (100 ml) was added with a solution of 1M potassium hydroxide. (42.6 ml). The mixture was refluxed under stirring for 3 h, after that was neutralized with 1M HCl and ethanol was evaporated off under reduced pressure. The resulting crude was suspended in water (30 ml) and extracted with ethyl acetate (4×30 ml). The organic phase was dried and the solvent was evaporated off under reduced pressure, to obtain 2.172 g of the title compound as a brown solid with melting point 125-127° C. (85% yield).