Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.C(Cl)Cl.[CH3:26][NH2:27]>C(O)C>[CH3:26][NH:27][C:20]([C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:21]
Reactant: Cc1ccc(-n2nc(C(=O)Cl)cc2-c2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(C)cc2)n1
Temperature: 25 °C

Procedure:
A solution of 0.50 g of 1-(4-methylphenyl)-5-(4-chlorophenyl)pyrazole-3-carboxylic acid chloride in ml of CH2Cl2 is added dropwise to 100 ml of a 33% solution of methylamine in ethanol. After stirring for hours at room temperature, the mixture is concentrated under vacuum, the residue is taken up with a mixture of 5% Na2CO3 +AcOEt, the organic phase is decanted, washed with a saturated solution of NaCl and dried over MgSO4 and the solvents are evaporated off. The residue is taken up in isopropyl ether and the crystals obtained are filtered off and dried under vacuum to give 0.44 g of the expected amide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Reactant: COc1ccccc1B(O)O
Product: COc1ccccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide and (2-methoxyphenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide as a grey solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (s, 1H), 8.49 (s, 2H), 8.01 (dd, J=1.5, 8.9 Hz, 1H), 7.80 (d, J=9.2 Hz, 1H), 7.61-7.51 (m, 1H), 7.33 (dd, J=1.4, 7.4 Hz, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.18-7.08 (m, 1H), 3.65 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CNS(=O)(=O)c1ccc(F)cc1CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.90 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (1.17 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.74 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C(O)(=O)[CH2:10][C:11]([OH:13])=[O:12].O.Cl>N1CCCCC1.N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5](/[CH:7]=[CH:10]/[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1ccc(Cl)s1
Yield: 81.7 %

Procedure:
The solution of 1 g (6.62 mmol) of 5-chloro-2-thiophenecarboxaldehyde and 1.38 g (13.23 mmol) of malonic acid in 0.07 ml of piperidine and 5 ml of pyridine is refluxed for 2 hours. The reaction solution is subsequently allowed to cool, then poured into 20 ml of water and acidified to pH 1 using 2N hydrochloric acid. The product which precipitates in the process is filtered off with suction and dried in a drying cabinet at 80° C., giving 1.02 g of (E)-3-(5-chlorothiophen-2-yl)acrylic acid as brown crystals, ESI 189. Analogously to Example 7.1, reaction between the compound of Example 7.2 and (E)-3-(5-chlorothiophen-2-yl)acrylic acid gives the compound N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-1-[(E)-3-(5-chlorothiophen-2-yl)acryloyl]-4-hydroxypyrrolidine-2-carboxamide as colourless crystals, ESI 476, m.p. 151°.
Reaction SMILES: O1CCOCC1.[CH2:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:15]1([NH:21]O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([NH:21][CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ONc1ccccc1
Reactant: C=CCCCCCC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCCCC/C=C/CNc1ccccc1
Yield: 95 %

Procedure:
A stirred mixture containing dioxane (12mL), 3 mL of 1-octene, 1g of 4A Molecular Sieves, and 0.051 g (0.11 mmol) of (2,6-diPicolinato)MoO2 (hexamethyl phosphoramide)is heated at reflux (ca. 100° C.) under a nitrogen atomosphere while a toluene solution (50 mL)of N-phenyl hydroxylamine (1.26 g, 11.6 mmol) is added dropwise over a 24 hr period. After heating an additional 6-12 hr, the mixture was allowed to cool and the volatiles were removed by evaporation at reduced pressure and the residue chromatographed over silica gel. Elution with pentane afforded phenyl trans-2-octenyl amine (>95% one isomer by NMR, GC/MS) in 20-30 % yield based on the hydroxylamine. Later fractions contained aniline, azobenzene and azoxybenzene.
Reaction SMILES: [Na+].[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21]([O-:23])=O)[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5].[CH2:36]([O:40][C:41]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:42]=1[CH2:43][NH2:44])[CH2:37][CH:38]=[CH2:39].C(OC1C=CC=CC=1CNC(C1N=C2C=C(C)C([C@H](OC(C)(C)C)C(OC)=O)=C(N3CCC(CCC=C)(C)CC3)N2C=1)=O)C=C>>[CH2:2]([C:6]1([CH3:35])[CH2:11][CH2:10][N:9]([C:12]2[N:17]3[CH:18]=[C:19]([C:21](=[O:23])[NH:44][CH2:43][C:42]4[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:41]=4[O:40][CH2:36][CH2:37][CH:38]=[CH2:39])[N:20]=[C:16]3[CH:15]=[C:14]([CH3:24])[C:13]=2[C@H:25]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])[C:26]([O:28][CH3:29])=[O:27])[CH2:8][CH2:7]1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Reactant: C=CCCOc1ccc(F)cc1CN
Agent: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)NCc4ccccc4OCC=C)cn23)CC1
Agent: [Na+]
Product: C=CCCOc1ccc(F)cc1CNC(=O)c1cn2c(N3CCC(C)(CCC=C)CC3)c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc2n1
Yield: 75 %

Procedure:
Prepared from (S)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylic acid sodium salt and 2-(but-3-en-1-yloxy)-5-fluorobenzylamine in 75% yield using the same procedure as (S)-methyl 2-(2-((2-(allyloxy)benzyl)carbamoyl)-5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (500 MHz, CDCl3) [note: appears to be 2:1 mixture of rotamers, major rotamer transcribed] δ 8.24-8.21 (m, 1H), 7.90-7.81 (m, 1H), 7.23-7.18 (m, 1H), 7.14-7.09 (m, 1H), 6.95-6.87 (m, 1H), 6.83-6.77 (m, 1H), 6.12-6.08 (m, 1H), 6.05-5.89 (m, 2H), 5.28-5.21 (m, 1H), 5.19-5.15 (m, 1H), 5.14-4.98 (m, 2H), 4.69-4.64 (m, 2H), 4.07 (s, 2H), 3.74-3.73 (m, 1H), 3.71 (s, 3H), 3.64-3.49 (m, 1H), 3.14-2.93 (m, 1H), 2.91-2.83 (m, 1H), 2.70-2.60 (m, 2H), 2.47-2.46 (m, 3H), 2.17-2.09 (m, 2H), 1.71-1.60 (m, 6H), 1.26 (s, 9H), 1.15 (s, 3H); LCMS (ESI, M+1): 649.35.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)=[C:11]([CH:14]=1)[C:12]#[N:13])([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([N:15]2[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]2)=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(O)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)ccc1N1CCC(O)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Ammonium chloride (1.2 g) and iron powder (6.3 g) were added to a mixed solvent of water (16 ml) and ethanol (48 ml), and the mixture was heated to 65° C. Then, 5-nitro-2-(4-hydroxypiperidino)benzonitrile (10 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (4.5 g), melting point: 144–145° C.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][PH:11](=[O:13])[CH3:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:10][P:11]([C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1)([CH3:12])=[O:13]
Reactant: Cc1cc(Br)ccc1N
Reactant: C[PH](C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: Cc1cc(P(C)(C)=O)ccc1N
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
To a solution of 4-bromo-2-methylaniline (0.372 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.313 g, 85% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25](Cl)=[O:26].C(N(CC)CC)C>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:15])([CH3:14])[CH2:12][NH:13][C:25]([C:17]2[O:16][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH:18]=2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: COc1ccc(C(C)(C)CN)cc1OC
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(C)(C)CNC(=O)c2cc3ccccc3o2)cc1OC
Reaction time: 15 h
Yield: 86.3 %

Procedure:
2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamine (106 mg, 0.506 mmol) and benzofuran-2-carbonyl chloride (90.7 mg, 0.502 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (139 μL, 1.00 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, redissolved in dichloromethane, and extracted with 1M hydrochloric acid, 1M sodium hydroxide, and a saturated aqueous solution of sodium chloride. The organic layer dried over sodium sulfate and evaporated to dryness. The crude product was then purified by column chromatography on silica gel using a gradient of 1-30% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (153 mg, 0.433 mmol, 86.3%). ESI-MS m/z calc. 353.2, found 354.2 (M+1)+. Retention time of 2.99 minutes. 1H NMR (400 MHz, CD3CN) δ 1.38 (s, 6H), 3.60 (s, 2H), 3.81 (s, 3H), 3.83 (s, 3H), 6.85-7.06 (m, 4H), 7.31-7.39 (m, 2H), 7.46 (t, J=8.4 Hz, 1H), 7.52-7.56 (m, 1H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[O:4][C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:6][C:7]=1[CH3:8].Cl.[NH2:20][OH:21].N1C=CN=C1>>[OH:21][N:20]1[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cc1ccc(Cc2cc(C)c(C)c(=O)o2)c(C)c1
Reactant: NO
Agent: Cl
Agent: c1c[nH]cn1
Product: Cc1ccc(Cc2cc(C)c(C)c(=O)n2O)c(C)c1
Yield: 59.3 %

Procedure:
1 g of 3,4-dimethyl-6-(2,4-dimethylbenzyl)-2-pyrone, 0.5 g of hydroxylamine hydrochloride and 3 g of imidazole were heated for 8 hours to 75° C and then worked up in the usual manner. There were obtained 0.63 g (59 %) of 1-hydroxy-3,4-dimethyl-6-(2,4-dimethylbenzyl)-2-pyridone melting at 141° C (Calc.: 5.4 % N; found: 5.6 % N). When using pyridine instead of imidazole under otherwise equal reaction conditions, the yield was 0.003 g (0.3 %).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][C:26]1([CH2:29]O)[CH2:28][CH2:27]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:29][C:26]3([NH:25][C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:24])[CH2:27][CH2:28]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCC1(NC(=O)OCc2ccccc2)CC1
Reaction time: 20 h
Yield: 46.2 %

Procedure:
20 ml of DCM were added with 4-chloro-7-hydroxy-6-methoxyquinoline (300 mg, 1.43 mmol; from China Gateway), 1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane (412 mg, 1.87 mmol, 1.3 eq; from China Gateway) and triphenylphosphine (490 mg, 1.87 mmol, 1.3 eq). The resulting solution was dropwise added with a solution of DEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperature at 0° C. for 2 hours. The mixture was then left at 10° C. for 20 hours, then filtered to recover the unreacted 4-chloro-7-hydroxy-6-methoxyquinoline. The filtrate was evaporated under vacuum and the resulting residue was added with 20 ml of 95% EtOH and left under stirring for 30 min. The solid was collected by filtration, washed with 5 ml of 95% EtOH and dried under vacuum to give 1-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (273 mg; yield: 46%).
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(C3CCOCC3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2C2CCOCC2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-5′-methoxy-2-(tetrahydro-2H-pyran-4-yl)biphenyl-4-yl)oxy)methyl)phenyl)propanoate (120 mg) in ethanol (3.0 mL) was added 2N aqueous sodium hydroxide solution (0.23 mL), and the mixture was stirred at 70° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (108 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>O1CCOCC1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(Cl)nc12
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NCc3cccnc3)nc12
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.9 %

Procedure:
To a solution of 2-chloro-4-methoxy-7-phenyl-benzothiazole (150 mg, 0.54 mmol), in dioxane (5 ml) was added 3-(aminomethyl)-pyridine (176 mg, 1.6 mmol) and this mixture was stirred at 100° C. for 18 h. The solvent was then evaporated and the mixture taken up in methanol (8 ml) and ultrasonnicated for 10 min. to precipitate the product, which was washed with methanol (5 ml), and dried under vacuum (0.05 mmHg, 60° C.) to afford the title compound as a white solid (58 mg, 31% yield), MS: m/e=348.3 (M+H+).
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]#[N:39]>C1COCC1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][CH2:37][C:38]#[N:39])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(OCC#N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Yield: 95.3 %

Procedure:
2.0 g (5.23 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1), 2.21 g of K2CO3, 0.26 g (1.57 mmol) of KI and 0.52 ml (7.85 mmol) of bromoacetonitrile were stirred in 30 ml of dry THF for 5 hours. The inorganic salts were filtered off and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in CH2Cl2 and the organic phase was washed with H2O, sat. sol. NaHCO3, sat. sol. NaCl, separated, dried over Na2SO4 and evaporated in vacuo to dryness to afford 2.10 g of a brown oil which was flash chromatographed on 230-400 mesh silica gel, eluting with a mixture of hexane/EtOAc 70:30. The crude product was triturated with hexane, filtered, washed and dried to yield 0.75 g of the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc2c1CCCC2
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Oc1cccc2c1CCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-naphthalen-1-ol (3.00 g, 20.24 mmol) and ethyl-2-butynoate (13.62 g, 121.46 mmol) in tetrahydrofuran (100 mL) was treated with potassium carbonate (3.10 g, 22.43 mmol) and 4-dimethylaminopyridine (0.26 g, 2.12 mmol). The reaction was then heated at 85° C. overnight. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL) and was washed with water (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with ethyl acetate and concentrated in vacuo. The material was taken up in ethyl acetate and absorbed onto silica gel. Purification by Analogix flash chromatography (115 g, 1-10% ethyl acetate/hexanes) afforded 3-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (3.82 g, 72%) as a light yellow oil: HR-ES-MS m/z calculated for C26H34N4O5 [M+H]+ 483.2602, observed 483.2603; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.1 Hz, 3H), 1.61-1.77 (m, 4H), 2.44 (s, 3H), 2.46 (br. s., 2H), 2.76 (br. s., 2H), 3.98 (q, J=7.1 Hz, 2H), 4.57 (s, 1H), 6.84 (d, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:27]#[N:28])=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12.C[Sn]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[C:27]4[NH:35][N:34]=[N:33][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccncc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccncc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methyl-2-propyl-3-[[4-(3-cyanopyridin-4-yl)phenyl]methyl]imidazo[4,5-b]pyridine (50 mg, 0.136 mmol) and trimethylstannylazide (84 mg, 0.408 mmol) in toluene (4 mL) was heated to reflux for 4 days. The mixture was cooled to rt, concentrated, then purified by flash chromatography on SiO2 (80/20/1 CH2Cl2 /MeOH/NH4OH) to give the product as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:17][C:18]([CH3:23])([CH2:21]O)[CH2:19][OH:20]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:17][C:18]1([CH3:23])[CH2:19][O:20][C:2]([CH2:3][S:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:1][CH2:21]1
Reactant: CCOC(=O)CSCC(=O)c1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CSCC1(c2ccccc2)OCC(C)(C)CO1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
Ethyl [(2-oxo-2-phenylethyl)thio]acetate (10.8 g, 45.3 mmol) was dissolved in toluene (250 ml). 2,2-Dimethyl-1,3-propanediol (37.6 g, 0.36 mol) and p-toluene sulfonic acid (cat., 500 mg) were added. The mixture was stirred at reflux in a Dean-Stark apparatus for two hours and at room temperature overnight. The mixture was concentrated under reduced pressure. The crude oil was purified by flash-chromatography (hexane:EtOAc-7:1) to give 11.2 g (70%) of the title compound as a colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.2-1.3 (t, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.2 (s, 2H), 3.5 (s, 4H), 4.1-4.2 (q, 2H), 7.3-7.6 (m, 5H).