Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](I)[CH:30]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:36])[NH:28][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([N:8]2[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=[C:7]2[CH2:6][C:5]2[CH:20]=[CH:21][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:34]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)Nc1cccc(I)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)c1

Procedure:
2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (1 g, 2.6 mmol) was treated with (3-iodo-phenyl)-carbamic acid tert-butyl ester following general procedure R to provide {3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-carbamic acid tert-butyl ester. The bromophenyl product (370 mg, 0.64 mmol) was treated as described in general procedure G using 4-ethoxycarbonylphenyl boronic acid to provide 4′-[1-(3-tert-butoxycarbonylamino-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazol-2-ylmethyl]-biphenyl-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](O[C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[NH3:17]>>[CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12](=[O:13])[NH:17][C:15](=[O:16])[CH:6]21)[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCCC12C=CC(C1)C1C(=O)NC(=O)C12

Procedure:
A mixture of 30 g of allylmethylbicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic anhydride, prepared in accordance with Example 2 of U.S. Pat. No. 3,105,839, and 10.2 g of 25% aqueous ammonia solution is heated at 100°-108° C. for 2.5 hours, with stirring and reflux cooling. According to a gas chromatogram, this gives a mixture of 12 isomers having varying positions for the allyl group and the methyl group in the 1-, 4-, 5- and 6-positions in the bicycloheptene ring, and also exo-anhydrides and endo-anhydrides. Since this mixture of isomers cannot be separated by fractional distillation, it is used for further purposes as such. Water is then removed by distillation, excess ammonia is expelled and the imide is rectified at 140°-145° C. and 2.0 Pa.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:16]N)[CH:13]=[CH:14][CH:15]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[C:7]3[C:2](=[O:1])[NH:3][CH:4]=[CH:5][C:6]=3[NH:16][C:12]=2[CH:11]=1
Reactant: Oc1ccnc(O)c1
Reactant: NNc1cccc(Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3cc(Cl)ccc3c12
Temperature: 175 °C
Reaction time: 3 h

Procedure:
To 2,4-dihydroxypyridine (25.0 g, 225 mmol) in phenyl ether (400 mL) in a three neck flask fitted with a Dean-Stark trap was added 3-chlorophenylhydrazine. The reaction mixture was heated to 175° C. for 1 h, and to 230° C. for 3 h. The reaction mixture was allowed to cool to room temperature and diluted with toluene. The mixture was filtered, washed with MeOH, and dried. The collected solids were ground to fine power, slurried in MeOH, and sonicated for 5 min. The slurry was filtered, washed with MeOH, and dried to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.83 (s, 1H); 11.19 (s, 1H); 8.05 (d, 1H); 7.53 (d, 1H); 7.32 (t, 1H); 7.21 (dd, 1H); 6.52 (d, 1H). LRMS (APCI) calc'd for (C11H7ClN2O) [M+H]+, 219.0. found 219.1.
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[N:4]=1.[Cl:25]CCl>>[Cl:25][C:17]1[C:11]2[C:12](=[N:13][CH:14]=[C:9]([C:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH2:18][CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:8]=[N:7][CH:6]=3)[CH:10]=2)[NH:15][CH:16]=1
Reactant: ClCCl
Reactant: CN(CC1CCOCC1)c1cncc(-c2cnc3[nH]ccc3c2)n1
Product: CN(CC1CCOCC1)c1cncc(-c2cnc3[nH]cc(Cl)c3c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound N-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2-amine (143) (20 mg, 1.0 eq) in dichloromethane (5 mL) was added n-chlorosuccinamide (2.0 eq) and the resulting reaction mixture was stirred at room temperature overnight. After completion of the reaction the solvents were removed and extracted into CH2Cl2. The organic layer was separated and the aqueous phase was extracted with CH2Cl2 to retain the crude material. The combined organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed by rotary evaporator. The crude material was purified by flash column with 100-200 mesh silica gel employing 40% EtOAc/hexane eluents to obtain the pure off-white coloured solid of 6-(3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine compound 144.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([O:13]C)=O)[CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[O:4]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: C1CCNC1
Reactant: COC(=O)C1CC2(CCN1)OCCO2
Product: O=C(C1CC2(CCN1)OCCO2)N1CCCC1
Temperature: 150 °C

Procedure:
A mixture of the product of stage (iv) (0.887 g) and pyrrolidine (2.2 ml) was heated at 150° C. in an autoclave for 2 h, allowed to cool to room temperature and evaporated to dryness giving an oil (1.27 g). This was purified by flash chromatography eluting with chloroformmethanol (9:1), to give an oil which crystallised on standing to give the title compound as a solid (841 mg), m.p. 72.5°-74.5°.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([NH2:15])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([NH:15][C:16](=[O:18])[CH3:17])[CH:11]=[C:12]([Cl:14])[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
200 ml of pyridine are added dropwise to 100 g of 3,5-dichlorophenylamine in 3000 ml of chloroform, followed by addition of 90 ml of acetic anhydride. The reaction mixture is stirred for 12 hours at room temperature. The solvents are evaporated off under reduced pressure and the residue obtained is recrystallized from 1000 ml of ethyl acetate; m.p.=182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2cc(Cl)ccc2=O)nc1

Procedure:
5-Chloro-2-pyridinol (2.26 g, 17.4 mmol), 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), copper (0.022 g, 0.35 mmol) and K2CO3 (2.66 g, 19.2 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc: CH2Cl220:80 to 50:50 gradient elution) to afford the title compound as a white solid.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[C:1]1([C:7]2[C:8]([NH2:9])=[N:17][C:15]3[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCc1ccccc1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3ccccc3)c(N)nc2n1

Procedure:
Following the procedure of Example 1, phenylacetonitrile was reacted with 2,4-diamino-5-pyrimidine-carboxaldehyde to give the title compound; mp 317-318° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:13][O:14][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: NCc1ccc(OCCCl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COCCOc1ccc(CN)cc1
Reaction time: 2 h

Procedure:
4-(2-Chloroethoxy)benzylamine (2.0 g; 0,11 mol) was dissolved in anhydrous toluene (50 ml). The reaction mixture was ice-cooled and sodium methoxide (0.59 g; 0.011 mol) dissolved in methanol (5 ml) was added thereto. When the addition was complete the mixture was left to stand for 2 hours at room temperature and filtered. Solvent was evaporated from the filtrate, to give an oily residue of good purity.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:20])[C:10]2[CH:11]=[C:12]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1.[Br:21]Br.Cl>ClCCl>[Br:21][C:14]1[C:9]2[O:8][CH2:7][C:6]([CH3:5])([CH3:20])[C:10]=2[CH:11]=[C:12]([C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH:13]=1
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccc2c(c1)C(C)(C)CO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Reaction time: 6 h
Yield: 107.2 %

Procedure:
To a solution of AlCl3 (1.5 g, 11.32 mmol) in dry dichloromethane (30 mL) was added dropwise at room temperature 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one (989 mg, 4.52 mmol) in dichloromethane (15 mL) followed by bromine (0.28 mL, 5.43 mmol) and the reaction stirred for 6 hours. 1N HCl was added slowly and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed successively with aq. K2CO3, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.44 g of 1-(7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one (91%). 1H NMR (300 MHz; CDCl3): δ 1.21 (d, J=6.9 Hz, 6H), 1.39 (s, 6H), 3.47 (m, 1H), 4.43 (s, 2H), 7.70 (s, 1H), 7.95 (s, 1H). e. 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=O)=[O:5].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[NH:6][C:4](=[O:5])[C:3]([C:2]([F:18])([F:17])[F:1])=[CH:15]2
Reactant: COc1ccc(NC(=O)CC(F)(F)F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(=O)c(C(F)(F)F)cc2c1
Temperature: 60 °C
Yield: 93.2 %

Procedure:
To a solution of 3,3,3-trifluoro-N-(2-formyl-4-methoxyphenyl)propanamide (5.30 g, 20.3 mmol) in DMF (100 mL) was added K2CO3 (14.0 g, 101 mmol). The mixture was heated to 60° C. for 1.5 hours. The mixture was diluted with EtOAc (200 mL) and filtered off. The filtrate was washed with H2O (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give the desired product (4.60 g, yield 94%). 1H NMR (CDCl3 300 MHz): δ 12.25 (brs, 1H), 8.18 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.25 (dd, J=9.0, 2.7 Hz, 1H), 7.02 (d, J=2.7 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1.[C:15](O)(=[O:22])[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.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:15]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:4]([CH3:14])[CH2:3]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of the alcohol of step A (0.81 g, 4.0 mmol), benzoic acid (0.74 g, 6.0 mmol) and triphenylphosphine (2.11 g, 8.0 mmol) in toluene (20 mL) was added DIAD (1.67 mL, 8.0 mmol). After being stirred at room temperature for 4 hours, the solution was concentrated. The residue was purified by flash chromatography eluting with 0%, 5% and 20% EtOAc/hexanes provided 1.0 g of the title compound. MS calculated (M+H)+ 308. found 308.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:11]([Cl:14])=[N:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31]>>[C:19]1([S:16]([NH:15][C:10]2[CH:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][C:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:31])=[N:6][C:5]=3[CH3:7])[CH:13]=[N:12][C:11]=2[Cl:14])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1nc(N)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1
Product: Cc1nc(NC(=O)c2ccco2)sc1-c1cnc(Cl)c(NS(=O)(=O)c2ccccc2)c1

Procedure:
Using an analogous method to that described in Example 51, N-[5-(2-amino-4-methyl-1,3-thiazol-5-yl)-2-chloropyridin-3-yl]benzenesulfonamide was reacted with 2-furoyl chloride. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 8.0 minutes); 1H NMR Spectrum: (DMSOd6+D2O) 8.57 (1H, d); 8.27 (1H, d); 8.05 (2H, d); 7.83 (1H, t); 7.76 (1H, d); 7.69 (2H, t); 6.75 (1H, d); 6.55 (1H, dd); 2.25 (3H, s); Mass Spectrum: M+H+ 475.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>C1COCC1>[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:16]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:17])[CH:18]=[CH:19][CH:20]=1
Reactant: Brc1nccs1
Reactant: O=Cc1cccc(Br)c1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1nccs1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-bromothiazole (0.088 mL, 0.985 mmol) in THF (2.99 mL) cooled to 0° C. was added isopropylmagnesium chloride (0.493 mL, 0.985 mmol). After 50 min, 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. After 12 hr, the reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a brown liquid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23]O)[N:22]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)[N:22]=1)[CH3:16]
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Reactant: CN(C)Cc1nc(CO)cs1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D] in concentrated hydrochloric acid, and then made basic and worked up, produces the title compound which is identical to the product prepared in Example 33.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][C:14]#[C:15][CH2:16][OH:17].O.[Na+].[Cl-]>C(Cl)Cl>[S:2]([O:17][CH2:16][C:15]#[C:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])(=[O:3])[CH3:1]
Reactant: OCC#CCOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Methanesulfonyl chloride (1.0 mL, 12.80 mmol) was added dropwise to a stirred solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (1.9232 g, 11.30 mmol) and TEA (2.5 mL, 17.85 mmol) in DCM (40 mL) at ° C. for five minutes. And then the resulting mixture was stirred at room temperature for 5.5 hours. Water (20 mL) was added, followed by addition of saturated aqueous NaCl solution (70 mL). The organic phase was separated and washed again with brine (60 mL), dried over Na2SO4, concentrated. The residue was separated by flash column chromatography on silica gel using 5-25% EtOAc/hexane to afford 1.542 g of product (yield 55%, oil), along with 400 mg of Di-4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl ether (yield 22%). 1H-NMR (CDCl3): δ 4.88 (t, J=1.8 Hz, 2 H), 4.76 (t, J=3.0-3.3 Hz, 1 H), 4.37-4.24 (m, 2 H), 3.80-3.76 (m, 1 H), 3.54-3.50 (m, 1 H), 3.11 (s, 3 H), 1.78-1.51 (m, 6 H).
Reaction SMILES: CC(S([NH:7][C@@H:8]([C:10]1[CH:11]=[N:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=1)[CH3:9])=O)(C)C.Cl>CO>[F:18][C:16]([F:17])([F:19])[C:13]1[N:12]=[CH:11][C:10]([C@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)nc1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(C(F)(F)F)nc1
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
To a solution of 2-methyl-N-{(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-2-propanesulfinamide (41.6 g, 141 mmol) in methyl alcohol (470 mL) at 0° C. was added hydrogen chloride (4.0 M in dioxane; 106 mL, 424 mmol). After 30 min, the mixture was concentrated to dryness. The residue was recrystallized using ethyl alcohol (15 mL) and ether (40 mL). The white solid was filtered and dried under reduced pressure to give the hydrochloride salt of the title compound (26.3 g). MS 191.2 (M+1). 1H NMR (500 MHz, CD3 OD): δ 8.83 (d, J=2.2 Hz, 1H); 8.17 (d, J=8.2 Hz, 1H); 7.93 (d, J=8.2 Hz, 1H); 4.69 (q, J=6.9 Hz, 1H); 1.70 (d, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=[O:12])=[CH:3][N:2]=1.[CH2:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>S(Cl)(Cl)=O.N1C=CC=CC=1>[C:1]1([C:14]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([O:13][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:12])=[CH:3][N:2]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1cnc(C(=O)O)c2ccccc12
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOC(=O)c1cnc(C(=O)OCCCCCCCCCCCCCCCC)c2ccccc12
Reaction time: 19 h

Procedure:
Isoquinoline-1,4-dicarboxylic acid (1.8 g, 5 mmol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.90 g, 12 mmol) in 1 ml of pyridine. After 19 h at room temperature, the precipitate is filtered off and the filtrate is evaporated to dryness. The resulting residue is crystallized in toluene/ethanol. The crystals obtained are purified by silica gel flash-column chromatography (dichloromethane). Thus the title compound, m.p. 80.7°-81.4°, is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]1.O>CN(C)C=O>[CH3:3][N:4]([CH:20]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)c1ccccc1
Reactant: BrC1C=CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)C1C=CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a suspension (10 ml) of sodium hydride (0.24 g, 10 mmoles) in dimethylformamide was added dropwise at 0° C. a dimethylformamide solution (1 ml) of N-methylbenzamide (1.35 g, 10 mmoles). After completion of the addition, the temperature was raised to room temperature, and after stirring for 15 minutes, 3-bromocycloheptene (1.75 g, 10 mmoles) was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, poured into water (20 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.92 g of N-methyl-N-(2-cycloheptenyl)benzamide [Compound (54)].
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:42]1[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=1>COCCOC>[F:31][C:28]1[CH:27]=[CH:26][C:25]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)[CH:7]2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:45]3[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=3)=[CH:33][CH:32]=2)=[CH:30][CH:29]=1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(-c3ccncc3)cc2)cc1
Temperature: 90 °C
Yield: 51.9 %

Procedure:
To a solution of 1-(4-bromobenzyl)-6-phenylmethoxy-2-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline (500 mg, 1 mmol) in ethylene glycol dimethyl ether (15 mL) was added potassium phosphate (2.12 g, 10 mmol) and pyridine-4-boronic acid (185 mg, 1.5 mmol). The reaction mixture was heated to 90° C. for 18 hours under nitrogen. The resulting mixture was concentrated and water added and extracted with ethyl acetate. The organic layer was dried using sodium sulfate, filtered and concentrated to give a crude black oil. The oil was purified by column chromatography (SiO2, 40% ethyl acetate/hexanes) to provide the title compound (260 mg, 50% yield): ES-MS (m/z) 501 [M+H]+, 1H NMR (CDCl3) δ 8.64 (d, 2H), 7.49 (m, 4H), 7.38 (m, 5H), 7.13 (d, 2H), 6.92 (t, 2H), 6.78 (m, 3H), 6.72 (s, 2H), 5.04 (s, 2H), 4.79 (t, 1H), 3.59 (m, 1H), 3.49 (m, 2H), 3.22 (m, 1H), 3.01 (m, 1H), 2.71 (t, 1H).
Reaction SMILES: [N:1]1C=CC=C(OC2C=C(C=C(C#N)C=2)N)C=1.N1C=CC=CC=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:1])=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: N#Cc1cc(N)cc(Oc2cccnc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(F)cc1

Procedure:
To a solution of 1 eq. (0.1 g, 0.473 mmol) of 3-(pyridin-3-yloxy)-5-cyano-aniline in 0.47 M in CH2Cl2 (1 mL) and 1.6 eq. of pyridine (0.56 g, 0.71 mmol) was added 3 eq. of 4-fluorobenzoyl chloride (0.225 g, 1.42 mmol) and the resultant mixture stirred at rt overnight. The reaction mixture was diluted with CH2Cl2, washed with sat. NaHCO3, dried (Na2SO4) and concentrated in vacuo. The resultant residue was diluted with toluene and concentrated in vacuo (5 times). Purification by chromatography over silica with 5% MeOH/CH2Cl2 as the eluant afforded 134 mg of a the desired title compound of Formula I, N-[3-cyano-5-(pyridin-3-yloxy)-phenyl]]-4-fluoro-benzamide, as a solid (85% yield). Mpt 169-172° C. MS (M−1) 332.3.