Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:17][O:18][CH2:19]Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][O:18][CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Product: COCOC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 59 using N-(tert-butoxycarbonyl)-4-hydroxypiperidine, sodium hydride and methoxymethylchloride, N-(tert-butoxycarbonyl)-4-methoxymethoxypiperidine was obtained. This was treated with trifluoroacetic acid-chloroform to give 4-methoxymethoxypiperidine, which was subjected to the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-fold equivalents of triethylamine to give the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][S:2]([O:22][CH2:21][C:13]1[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]=1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: OCc1oc2ccccc2c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (160 μL, 2.05 mmol) was added dropwise to a solution of (3-phenylbenzofuran-2-yl)methanol (367 mg, 1.64 mmol) and DIPEA (343 μL, 1.97 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture was slowly warmed to RT. After 2 h stirring at RT, additional amounts of methanesulfonyl chloride (80 μL, 1.03 mmol) and DIPEA (172 μL, 0.99 mmol) were added and stirring was continued for 1.5 h. The reaction mixture was diluted with DCM and the organic layer was washed with water, then dried (Na2SO4) and concentrated in vacuo affording (3-phenylbenzofuran-2-yl)methyl methanesulfonate as an oil (443 mg, 89%). 1H NMR (DMSO, 400 MHz): δ 7.71-7.64 (2H, m), 7.62-7.56 (4H, m), 7.52-7.41 (2H, m), 7.37-7.32 (1H, m), 4.98 (2H, s), 3.89 (3H, s)
Reaction SMILES: [N:1]1([C:7]2[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[C:9]([C:15]([F:18])([F:17])[F:16])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1N=CN([C:24]([N:26]2C=N[CH:28]=[CH:27]2)=[O:25])C=1.NC1C2[O:38][CH2:39][C:40](=[O:42])[NH:41][C:36]=2[CH:35]=[CH:34][CH:33]=1>C1COCC1.CN(C=O)C>[O:42]=[C:40]1[NH:41][C:36]2[CH:35]=[CH:34][CH:33]=[C:27]([NH:26][C:24]([NH:14][CH2:13][C:12]3[C:7]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[N:8][C:9]([C:15]([F:18])([F:16])[F:17])=[CH:10][CH:11]=3)=[O:25])[C:28]=2[O:38][CH2:39]1
Reactant: NCc1ccc(C(F)(F)F)nc1N1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cccc2c1OCC(=O)N2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)nc2N2CCCCC2)N1
Temperature: 100 °C
Yield: 13 %

Procedure:
To a solution of 29f (0.48 g, 1.85 mmol) in THF (20 mL) was added CDI (2.1 mol eq, 0.63 g) and the mixture was heated for 5 h. The reaction mixture was evaporated, water was added and the aqueous phase was extracted with EtOAc (3×20 mL). The recombined organic phases were anhydrified over Na2SO4 and evaporated at reduced pressure. The oil obtained (0.78 g, quantitative yield) was dissolved in DMF (20 mL) and the bicyclic amine 1f was added (0.8 mol eq, 0.23 g), then the mixture obtained was heated at 100° C. overnight. The solvent was removed at reduced pressure and the residue was purified by chromatography (1:1 EtoAc:petroleum ether) to obtain the product as a pale yellow solid (0.067 g, 13% Yield). 1HNMR (DMSO, 400 MHz) δ 1.62 (m, 6H), 3.09 (m, 4H), 4.33 (d, 2H, J=6), 4.62 (s, 2H), 6.46 (dd, 1H, J=2), 6.81 (t, 1H, J=8), 7.42 (bt, 1H), 4.46 (d, 1H, J=8), 7.74 (m, 2H), 8.20 (s, 1H), 10.66 (s, 1H). [M+1] 450.02 (C21H22F3N5O3 requires 449.43).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:20])[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].[CH2:23]1COC[CH2:24]1>>[CH2:1]([O:8][CH2:9][C:10]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([OH:20])[CH:23]=[CH2:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(COCc1ccccc1)COCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7.4 g (27.4 mmol) of 1,3-bis(benzyloxy)-propan-2-one (Araki Y. et al., J. Chem. Soc., Perkin Trans. 1, 1981, 19) in 25 ml of THF was added dropwise at 10° C. and the mixture was stirred at ambient temperature for 2 h. Then 8 ml of a 20% aqueous NH4Cl solution was added, and the organic phase was evaporated, dissolved in ether, dried with MgSO4, and evaporated in vacuum to give 7.90 g of 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol as a crude oil.
Reaction SMILES: [CH3:1][O:2]C1C=C(C2C(N3CCNCC3)=C3C=CNC3=NC=2)C=CC=1.[C:24]([O:28][C:29]([N:31]([CH:44]([CH3:46])[CH3:45])C[C@H](C1C=CC(Cl)=CC=1)C(O)=O)=[O:30])([CH3:27])(C)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:2]=[CH:1][CH2:27][CH2:24][O:28][C:29](=[O:30])[NH:31][CH:44]([CH3:45])[CH3:46]
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCNCC2)c1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)OCCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 213 %

Procedure:
5-(3-Methoxyphenyl)-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyri dine (0.045 g, 0.118 mmol, see Example 8) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0424 g, 0.124 mmol, see Example H) were placed in DCM (3 mL). HOBT-H2O (0.0253 g, 0.165 mmol), EDCI (0.0294 g, 0.153 mmol), and DIEA (d 0.742; 0.103 mL, 0.590 mmol) were then added, and the reaction was stirred at room temperature for 2 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The product was dried, filtered, and concentrated to give the crude product. The crude product was purified (500:5 DCM:MeOH) to yield (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2, 3-1)]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 53.6% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]1([CH3:22])[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[N:3]([C:16]2[CH:17]=[CH:18][C:13]([CH3:22])=[CH:14][CH:15]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 48 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-tolylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methylphenyl)-1H-indole-3-carboxaldehyde (48% yield) as a cream solid. ESI/MS 270 (M+H), 311 [(M+1+CH3CN) adduct]: RT 3.55 min.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4].BrC[C:19]1[CH:20]=[C:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1.[H-].[Na+].[CH3:40]N(C)C(=O)C>>[C:34]([O:33][C:31]([C:21]1[CH:20]=[CH:19][CH:24]=[CH:23][C:22]=1[C:25]1[CH:26]=[CH:27][C:28]([CH2:40][N:6]2[C:7]([C:15]#[N:16])=[C:8]([C:10](=[O:14])[CH2:11][CH2:12][CH3:13])[N:9]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:29][CH:30]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CCCCc1nc(C(=O)CCC)c(C#N)[nH]1
Reactant: CC(=O)N(C)C
Reactant: CC(C)(C)OC(=O)c1cc(CBr)ccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc(C(=O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
Following a procedure similar to that described in Example 45(a), but using 0.877 g of 2-butyl-4-butyryl imidazole-5-carbonitrile (prepared as described in Preparation 26), 1.53 g of t-butyl 4-(bromomethyl )-biphenyl-2-carboxylate and 0.175 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 18 ml of N,N-dimethylacetamide, 0.99 g of the title compound was obtained as a viscous oil.
Reaction SMILES: C([C:3]1[N:4]=[C:5](Cl)[C:6]2[NH:11][CH:10]=[CH:9][C:7]=2[N:8]=1)C.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([CH:22]=1)[C:19]([O-:21])=[O:20].CN1CC[CH2:33][C:32]1=O.C(O)C>O>[O:23]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:5]2[C:6]3[NH:11][CH:10]=[CH:9][C:7]=3[N:8]=[CH:3][N:4]=2)=[CH:22][C:18]=1[C:19]([O:21][CH2:32][CH3:33])=[O:20])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1nc(Cl)c2[nH]ccc2n1
Reactant: Nc1ccc(Oc2ccccc2)c(C(=O)[O-])c1
Reactant: CN1CCCC1=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(Nc2ncnc3cc[nH]c23)ccc1Oc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (461 mg), 5-amino-2-phenoxybenzoate (926 mg) and 1-methyl-2-pyrrolidone (5 mL) was stirred at 80° C. for 2 hrs. Ethanol, water and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, and the solvent was evaporated under reduced pressure. Aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80) and recrystallized from ethanol-ethyl acetate to give the title compound (572 mg) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: C1=COCCC1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1ncnc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of 6-bromo-9H-purine (5.0 g, 25 mmol) and p-toluenesulfonic acid monohydrate (0.48 g, 2.5 mmol) in chloroform (100 mL) was cooled to 0° C., treated with dihydropyran (3.4 mL, 38 mmol) and stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate, water and brine, dried with MgSO4, filtered, concentrated and purified on silica gel (eluting with 0-50% of ethyl acetate in hexanes) to give the desired product (7.0 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][O:7]2.[I:12]I>CO.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]([I:12])[CH2:5][CH2:6][O:7]2
Reactant: II
Reactant: Clc1cccc2c1CCCO2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: Clc1cccc2c1C(I)CCO2
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of 5-chlorochroman (0.101 g; 0.6 mmol) and silver nitrate (0.112 g; 0.66 mmol) in methanol (6 mL) was added iodine (0.153 g; 0.6 mmol) and the reaction mixture for 30 min. The reaction was quenched by adding a solution of sodium thiosulphate 0.5M (2.5 mL) and the aqueous layer was extracted with ethyl acetate. The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-80%) in heptane furnished 0.088 g (50%) of 5-chloro-4-iodochroman.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[N:14]([CH2:19][CH:20]([F:22])[F:21])[C:13](=[O:23])[CH2:12][CH2:11]2)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[N:14]([CH2:19][CH:20]([F:22])[F:21])[C:13](=[O:23])[CH2:12][CH2:11]2
Reactant: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CCC(=O)N2CC(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc2c(cc1N)CCC(=O)N2CC(F)F
Reaction time: 2 h
Yield: 88.4 %

Procedure:
The compound (2.29 g, 6.73 mmol) of step C was dissolved in dichloromethane (15 ml), 4N hydrochloric acid-dioxane solution (15 ml, 60 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and the organic layer was dried over saturated brine. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.43 g, yield 88%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]#[N:12])=[C:9]([O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[C:11]([C:10]1[C:4]2[S:3][C:2]([NH:1][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])=[N:6][C:5]=2[CH:7]=[CH:8][C:9]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:23])[F:24])[CH:15]=1)#[N:12]
Reactant: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a solution of N-{3-[(2-amino-7-cyano-1,3-benzothiazol-6-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (1.5 g, 3.96 mmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (467 μL, 5.15 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→60/40), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (1.26 g, 63%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6](Cl)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]2[CH:6]([N:27]3[CH2:26][CH2:25][N:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]3)[CH2:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cc1Cl)C(Cl)Cc1ccccc1S2
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(C2Cc3ccccc3Sc3cc(Cl)c(Cl)cc32)CC1
Yield: 82 %

Procedure:
A mixture of 7,8,10-trichloro-10,11-dihydrodibenzo(b,f)thiepine (the preparation of which is described in Example 8) (9.5 g) and 1-ethoxycarbonylpiperazine (11.9 g) was heated to 110°-120° C. for 4 hours. The preparation of the reaction mixture is analogous to that used in the preparation of the final base in Example 8 and yields 10.8 g (82%) of an oily base which was dissolved in ethanol and neutralized with maleic acid. Addition of either precipitates the maleate, C25H26Cl2N2O6S which is crystallized from a ten-fold amount of ethanol and melts at 184°-186° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:5][CH:4]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1>[Cl:22][CH2:23][C:24]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:17][C:16]3([CH3:19])[CH2:18][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15]3)=[O:10])=[CH:7][CH:8]=1)=[O:25]
Reactant: CNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: CN(C(=O)CCl)c1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 1.25 h
Yield: 52.5 %

Procedure:
To a mixture of (4-methylamino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (0.6 g, 2.1 mmol) and TEA (0.6 ml, 4.19 mmol) in dry THF (40 ml) was added dropwise chloroacetyl chloride (0.25 ml, 3.14 mmol). The mixture was stirred for 75 min. and evaporated in vacuo followed by addition of water 75 (ml). The aqueous phase was extracted with EtOAc (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on column chromatography (silicagel) using EtOAc-Heptane 1:1 as eluent. Pure fractions were collected; the solvent evaporated in vacuo affording 400 mg (53%) of 2-chloro-N-methyl-N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acetamide as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[N+](=[CH2:15])=[N-].CO>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:15])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Nitrobenzoic acid (Aldrich)(1 g; 5.98 mmol; 1 eq.) is dissolved in toluene (15 ml). Timethylsilyl diazomethane in toluene and MeOH (1/1)(9.0 ml; 2 M; 17.95 mmol; 3 eq.) is added dropwise. The solution is stirred at rt for 1.5 h. Solvents are removed affording methyl 3-nitrobenzoate as a yellow powder (940.7 mg; 87%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[O:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:13]
Reactant: OB(O)c1ccco1
Reactant: COC(=O)c1cc(Cl)nc(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C=O)nc(-c2ccco2)c1
Temperature: 55 °C
Reaction time: 14 h
Yield: 42.5 %

Procedure:
To a degassed mixture of 205 mg (1.027 mmol) of methyl 2-chloro-6-formylisonicotinate, 183 mg (1.64 mmol) of 2-furanboronic acid, and 316 mg (2.98 mmol) of Na2CO3 in 2 mL of H2O and 4 mL of THF was added 263 mg (0.227 mmol) of Pd(PPh3)4. The mixture was stirred at 55° C. for 14 h, and EtOAc and H2O were added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided methyl 2-formyl-6-(furan-2-yl)isonicotinate as a yellow solid (101 mg) in 43% yield. The desired 6-(furan-2-yl)-4-(methoxycarbonyl)picolinic acid was synthesized from the aldehyde (methyl 2-formyl-6-(furan-2-yl)isonicotinate) following the general procedures as described herein.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][C:7]=2[N:8]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[C:27]=1[Cl:32]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:32][C:27]1[C:28]([CH3:31])=[N:29][S:30][C:26]=1[NH:25][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:6]2[O:5][C:4]([CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])=[N:8][C:7]=2[CH:9]=1
Reactant: CC(C)(C)Cc1nc2cc(CC(=O)O)ccc2o1
Reactant: Cc1nsc(N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)Cc2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.7 %

Procedure:
[2-(2,2-Dimethylpropyl)benzoxazol-5-yl]acetic acid [from step 7] (0.800 g, 0.003 mole) was suspended in dichloromethane (10 ml) and N,N-dimethylformamide (one drop) and oxalyl chloride (0.451 g, 0.004 mole) were added sequentially. The mixture was stirred for 2 hour and then the solvent was removed in vacuo. The residue was taken up in xylene (10 ml), 5-amino-4-chloro-3-methylisothiazole [from step 1] (0.829 g, 0.006 mole) was added and then the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was further purified by flash column chromatography on silica gel, eluting with a 2:1 mixture of hexane:ethyl acetate, to give N-(4-chloro-3-methylisothiazol-5-yl)-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.325 g) as a pale orange solid, m.p. 144-145° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.C([O:21][C:22](=O)[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C>C(O)C>[OH:30][C:23]1[C:22](=[O:21])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:14]([C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=2)[C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: NCCCn1ccnc1
Reactant: O=Cc1cccc(O)c1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1cccc(O)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3-Hydroxy-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([C:22](OC)=[O:23])=[CH:15][C:13]=2[N:14]=1.[BH4-].[Li+].O1CCCC1>C(OCC)C>[C:1]1([CH3:26])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[S:11][C:12]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:16]([CH2:22][OH:23])=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c2sc(Nc3c(C)cc(C)cc3C)nc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(Nc2nc3cc(CO)cc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.4 %

Procedure:
To a solution of methyl 2-mesitylamino-7-nitro-1,3-benzothiazole-5-carboxylate (350 mg, 0.942 mmol) in ethyl ether (6 ml) was added 2.0 M solution of lithium borohydride in tetrahydrofuran (THF) (1.41 ml, 2.82 mmol). The mixture was stirred at room temperature for 15 h. The reaction was quenched with saturated NH4Cl solution. The aqueous phase was extracted with ethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under vacuum. The residue was purified by chromatography eluting with 20% AcOEt in n-hexane to afford 189 mg of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29]>CC(=O)CC>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: OCCCCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1ccc(-c2ccc(OCCCCCCO)cc2)cc1
Yield: 66.4 %

Procedure:
A solution of 0.10 g (0.51 mmol) of 4-cyano-4'-hydroxybiphenyl and 0.10 g (0.72 mmol) of potassium carbonate dissolved in 4 ml of 2-butanone was refluxed. After addition of 0.10 g (0.55 mmol) of 6-bromohexan-1-ol to the reaction mixture, the whole was refluxed overnight. After removal of the solvent by distillation, water was added to the residue and the whole was extracted with methylene chloride. The extract was purified by silica gel column chromatography. The resulting white solid was recrystallized from hexane to obtain 0.10 g of 4-cyano-4'(6-hydroxyhexyloxy)biphenyl (9) (yield: 66.4%).