Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].C(=O)(O)[O-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([NH:19][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[N:10]([CH2:16][CH:17]=[CH2:18])[CH2:9]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCN1CC(c2ccc(N)cc2F)CCS1(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1CC(c2ccc(NC(=O)OCc3ccccc3)cc2F)CCS1(=O)=O
Yield: 100.1 %

Procedure:
3-fluoro-4-[tetrahydro-1,1-dioxido-2-(2-propenyl)-2H-1,2-thiazin-4-yl]benzenamine (1.154 g, 4.06 mmol) is dissolved in THF (15 ml) to which is added benzyl chloroformate (765 mg, 4.48 mmol) followed by a solution of sodium bicarbonate (700 mg, 8.33 mmol) in water (10 ml). After stirring for 2 hr most of the THF is evaporated and the residue is extracted with ethyl acetate (100 ml). After washing with water (25 ml) and brine, the solution is dried (MgSO4) and evaporated to afford the title compound as white crystals (1.70 g, 100%) mp 138-140°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>ClCCl>[C:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][O:10][N:9]=2)=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: O=C(O)c1conc1-c1ccc(O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2nocc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution (120 ml) of 3-(4-hydroxyphenyl)isoxazole-4-carboxylic acid (1.39 g, 6.77 mmol) in dichloromethane were added acetic anhydride (2.07 g, 20.28 mmol), triethylamine (3.43 g, 33.90 mmol), and 4-N,N-dimethylaminopyridine (84 mg, 0.676 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and water was added. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound (1.50 g, 78%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CC(C)OC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed. The filtrate was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica, eluting firstly with 0 to 10% v/v methanol/dichloromethane and then toluene/ethyl acetate/.880 ammonium hydroxide/ethanol (60:20:10:35 v/v/v/v), gave a cream solid. Recrystallisation from iso-propanol gave the title compound, 2.1 g: m.p. 121°-122° C.; NMR (d6DMSO) δ 8.14 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.99 (1H, m), 4.85 (2H, s), 3.84 (2H, s), 3.33 (4H, t), 2.62 (4H, t), 1.22 (6H, d); m/e 398 (M+H)+ ; calculated for C22H27N3O4 : C, 66.5; H, 6.9; N, 10.6. found: C, 65.8; H, 6.8; N, 10.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:25][CH2:24][CH2:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CCC2)cc1
Temperature: 3 °C

Procedure:
1-(4-Chlorophenyl)cyclobutanecarboxylic acid (6.63 g, 31.492 mmol) and 2-(4-methoxyphenyl)ethanamine (5.00 g, 33.067 mmol) were treated with dichloromethane (470 mL). The suspension was cooled to 3° C. and N,N-dimethylpyridin-4-amine (4.04 g, 33.1 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (6.35 g, 33.1 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred over night. The reaction mixture was washed successively with 2N hydrochloric acid (2×) and water (2×). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash-chromatography (silica, dichloromethane:methanol=9:1) to give a pale yellow solid. Yield: 10.58 g (30.8 mmol, 98%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[CH2:3][NH:2]1.[CH3:19][N:20]=[C:21]=[S:22]>C1C=CC=CC=1>[CH3:19][NH:20][C:21]([N:2]1[CH2:3][C:4]2([CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[O:11]2)[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[S:22]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: CN=C=S
Solvent: c1ccccc1
Product: CNC(=S)N1Cc2ccccc2C2(Cc3ccccc3O2)C1
Reaction time: 1 h

Procedure:
To a stirred solution of spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (5.0 g) in dry benzene (18 ml) is added methylisothiocyanate (3.1 g) in dry benzene (10 ml). After one hour, the product begins to separate. The mixture is stirred overnight and diluted with hexane (18 ml). The product is filtered, washed with hexane and dried to yield a solid. The solid is twice recrystallized from benzene to yield (3.0 g, 46%) as a solid, mp 165°-166°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=[C:4]2[C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:4]3[N:5]([C:8](=[O:15])[N:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:29][C:28]=2[Cl:30])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)ccn2c1=O
Temperature: 200 °C
Yield: 32 %

Procedure:
To a stirring, degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-isobutyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (20 mg, 0.05 mmol), 2,4-dichlorophenylboronic acid (38 mg, 0.20 mmol), and tetrakis(triphenylphosphine)palladium (3 mg, 0.002 mmol) in dioxane (0.4 mL) at 20° C. was added K2CO3 (30 mg, 0.2 mmol) in water (0.13 mL). The resulting reaction mixture was heated in a microwave reactor at 200° C. for 10 min under argon. Analysis by HPLC/MS indicated that starting material had been consumed. The reaction mixture was brought to room temperature and was concentrated under reduced pressure. The crude product was purified by reverse phase preparative HPLC (acetonitrile-water-TFA) to isolate the title compound (7 mg, 0.016 mmol) as a yellow oil. MS: [M+H]+=446.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[NH2:8][C:6]1[C:5]([NH:9][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc(Cl)nc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(Cl)nc1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.9 %

Procedure:
A stirred mixture of 6-chloropyridine-2,3-diamine (E-24) (7.2 g, 50 mol, 1.0 eq) and potassium carbonate (6.9 g, 50 mmol, 1 eq) in DMF (100 mL) was stirred for 30 min and then ethyl bromoacetate (9.2 g, 55 mmol, 1.1 eq) was added, the resulting mixture was stirred at 60-70° C. for 3 h. The reaction was complete based on TLC analysis. The reaction mixture was poured into ice-water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to afford the desired product ethyl 2-(2-amino-6-chloropyridin-3-ylamino)acetate (E-25) (5.8 g, 50.5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ: 6.39 (m, 2H), 5.93 (bs, 2H), 5.32 (m, 1H), 4.08 (m, 2H), 3.88 (d, J=6.0 Hz, 2H), 1.15 (m, 3H); ESI-MS m/z: 230.05 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[CH2:1]([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-:33])=[CH:13][C:12]=2[N:11]=[C:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COn2c(-c3ccccc3)nc3cnc4ccccc4c32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc2nc(-c3ccccc3)n(OCc3ccccc3)c2c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 125.5 %

Procedure:
1-(Benzyloxy)-2-phenyl-1H-imidazo[4,5-c]quinoline (0.951 g, 2.71 mmol) was combined with 3-chloroperoxybenzoic acid (1.2 g of 77% pure material, 5.4 mmol) in dichloromethane (10 mL) and stirred at room temperature for 30 minutes. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material; additional 3-chloroperoxybenzoic acid (0.1 g) was added. The reaction mixture was stirred for 18 hours at room temperature and then diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide 1.25 g of 1-(benzyloxy)-5-oxido-2-phenyl-1H-imidazo[4,5-c]quinoline as a black oil. Attempts to obtain a solid by trituration with hexane/diethyl ether and hexane were unsuccessful.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH:7]=1
Reactant: C1CCNC1
Reactant: O=c1[nH]c(-c2cc(Br)ccc2F)nc2nccnc12
Product: O=c1[nH]c(-c2cc(Br)ccc2N2CCCC2)nc2nccnc12

Procedure:
A solution of 2-(5-bromo-2-fluorophenyl)pteridin-4-one 104 in pyrrolidine was heated in a microwave cavity (Power=270 W, Temp=110° C.) for 12 min. The pyrrolidine was evaporated, then residue partitioned between NaHCO3 0.5 N and CH2Cl2, dried (Na2SO4) and evaporated. Trituration in Et2O afforded the title product 110 as a yellow powder (LCMS analysis).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[SH:12].Cl[C:14]1[S:15][C:16]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:17]=2[N:18]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:16]2[S:15][C:14]([S:12][C:4]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])=[N:18][C:17]=2[CH:19]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S
Reactant: Clc1ccc2sc(Cl)nc2c1
Product: COc1cc([N+](=O)[O-])ccc1Sc1nc2cc(Cl)ccc2s1

Procedure:
5-Chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257) was prepared (75%) from 2-methoxy-4-nitrobenzenethiol (249) and 2,5-dichlorobenzothiazole (250), in a similar manner as described in example 251.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][N:6]2[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=12.[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][NH:25][C:24](=[O:27])[CH2:23]1.CN(C=O)C.[H-].[Na+]>O>[F:19][C:20]([F:28])=[CH:21][CH:22]1[CH2:26][N:25]([CH2:2][C:3]2[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:5][N:6]3[CH:11]=[C:10]([CH3:12])[CH:9]=[N:8][C:7]=23)[C:24](=[O:27])[CH2:23]1
Reactant: Cc1cnc2c(CCl)c(-c3ccccc3)nn2c1
Reactant: O=C1CC(C=C(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(CN3CC(C=C(F)F)CC3=O)c(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
The above mentioned solution of intermediate x146 is added to a solution containing 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.64 mmol, 1.1 eq, 0.356 g), 6 ml of dry DMF and sodium hydride (60% dispersion in oil, 2.64 mmol, 1.1 eq, 0.1 g) that have been stirred at room temperature for 0.5 hour. The resulting mixture is heated up at 80° C. for 1 hour. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue is crystallized in AcOEt to afford 0.443 g of 4-(2,2-difluorovinyl)-1-[(6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]pyrrolidin-2-one 211.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH:28]=1>>[CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH:28]=1)=[O:5]
Reactant: CC(Cc1ccccc1)C(=O)O
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Product: CC(Cc1ccccc1)C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1
Yield: 75 %

Procedure:
Similarly prepared as per compound 8 procedure, using starting materials 2-methyl-3-phenylpropanoic acid and compound 4 to obtained title compound as white solid (75%). 1H NMR (CDCl3, 400 MHz) δ 1.29 (d, J=6 Hz, 3H), 2.63 (q, J=6.4 Hz, 1H), 2.77 (dd, J1=16 Hz, J2=5.6 Hz, 1H), 3.02 (dd, J1=16 Hz, J2=9.2 Hz, 1H), 7.17-7.25 (m, 5H), 7.34-7.44 (m, 3H), 7.75 (s, 1H), 7.99 (d, J=4 Hz, 2H), 8.75 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.0, 40.9, 44.9, 110.9, 112.5, 120.0, 121.2, 126.7, 128.8, 129.1, 134.4, 135.3, 139.8, 142.1, 147.8, 150.8, 174.3; ESI-HRMS for C22H20N3O2 (M+H)+ calcd. 358.1556 found 358.1556.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)(=[O:28])=[O:27])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with thiophene-2-sulfonyl chloride (0.192 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 1.75 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL) and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.322 g), mp 211-213° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:16]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([O:35]CC)=[O:34].[OH-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)[N:16]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[O:31][CH2:32][C:33]([OH:35])=[O:34]
Reactant: CCCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2.5 h
Yield: 73.1 %

Procedure:
To a solution of ethyl ({2-methyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}hexyl)oxy]phenyl}oxy)acetate (80 mg, 0.16 mmol) in MeOH (2 mL) and THF (2 mL) at rt was added aqueous NaOH (2M, 1 mL, 2.0 mmol) and the resulting mixture stirred for 2.5 hours. The solvents were then removed under vacuum and the residue partitioned between DCM (20 mL) and aqueous HCl (2M, 20 mL), the layers separated and the aqueous re-extracted with DCM (20 mL). The combined organic solution was passed through a hydrophobic frit and then reduced affording the title compound as colourless oil (57 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH:40]=O)[CH2:36][CH2:35]1)(=[O:33])=[O:32].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:40][CH:37]3[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)N1CCC(C=O)CC1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC1CCN(S(C)(=O)=O)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Reaction time: 2 h
Yield: 62.9 %

Procedure:
(S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamine (24 grams, 0.117 mole) was dissolved in dichloroethane (300 ml) and sodium triacetoxyborohydride (37.2 grams, 0.176 mole) was added. After stirring for 5 minutes N-methanesulfonylpiperidine-4-carboxaldehyde (22.4 grams, 0.117 mole) was added and the mixture was stirred for another 2 hours. 5% sodium carbonate (600 ml) was added and the mixture was extracted with dichloromethane. Evaporation of the solvent gave an oil which was recrystallized from ether to give (S)-N-[2-(2,3,-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-methanesulfonylpiperidin-4-ylmethyl)amine (28 grams, 63%), m.p. 99-101° C.
Reaction SMILES: [CH2:1]([C:3](O)([CH:6]([CH3:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:4]=[CH2:5])[CH3:2].P(Br)(Br)[Br:15]>>[Br:15][CH2:2][CH:1]=[C:3]([CH2:4][CH3:5])[CH:6]([CH3:12])[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: BrP(Br)Br
Reactant: C=CC(O)(CC)C(C)CC=C(C)C
Product: CCC(=CCBr)C(C)CC=C(C)C

Procedure:
Following the procedure of Example 9, 3-ethyl-4,7-dimethyl-1,6-octadien-3-ol and phosphorus tribromide are reacted to form 1-bromo-3-ethyl-4,7-dimethyl-2,6-octadiene.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CO>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][N:28]=4)[C:23]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([Cl:31])=[CH:33][CH:34]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)O)ccn1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cc(C(=O)Nc2ccc(Cl)cc2)ccn1
Yield: 96.9 %

Procedure:
To solution of 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-isonicotinic acid (40 mg, 0.098 mmol), 4-chloroaniline (25.12 mg, 0.196 mmol) and DMAP (21.65 mg, 0.17 mmol) in DMF was added PyBOP (92.22 mg, 0.17 mmol), and stirred. Reaction mixture was poured onto ice cold water, diluted by methanol/MC mixture (10%). The organic phase was separated, sequentially washed with aqueous sodium bicarbonate, brine and water, dried over anhydrous MgSO4, and concentrated. The resultant crude product was purified by PLC (MeOH:MC=1:9) to afford 2-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-(4-chloro-phenyl)-isonicotinamide as a colorless solid (49 mg, 98% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([O:14]C(C)(C)C)=[O:13])=[CH:5][CH:4]=1)#[N:2].CO>O.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 34.7 %

Procedure:
A round bottom flask was charged with 21B (11.6 g, 47.7 mmol, 1 eq) and MeOH (55 mL). With moderate stirring, a solution was formed. To the solution was added a solution of NaOH (5.7 g, 143.1 mmol, 3 eqs) in H2O (30 mL). The resulting mixture was heated in an oil bath at a temperature of 70° C. for 4 h. The reaction mixture was analyzed for completion using 1H NMR. After confirming completion of the reaction, the reaction mixture was concentrated to one-third its volume and the rest of the reaction mixture was diluted by the addition of 50 mL of a NaOH (0.5 M) solution. The resulting mixture was washed with 2×25 mL of MTBE. The aq. layer was separated and acidified by the dropwise addition of conc. HCl until the pH of the mixture was ˜1. The acidified mixture was extracted with 2×50 mL of EtOAc. The combined organic extracts were dried over MgSO4 and evaporated to dryness on a rotary evaporator to give crude product. The crude product was purified by flash chromatography, eluting with 1-10% MeOH in DCM. The product was isolated as a single spot on TLC. However, 1H NMR analysis of this product indicated a small amount of impurities were present. This material was then dissolved in a 1 M solution of NaOH (30 mL) and washed with 2×25 mL of EtOAc. The aq. layer was separated and re-acidified to pH ˜1 by the dropwise addition of conc. HCl. The mixture formed was extracted with EtOAc (50 mL). The organic extract was evaporated to dryness to give 3.1 g 21C as a white solid (36.4% yield). Note: a very small amount of impurities were still present in the material, as revealed by 1H NMR. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.37-1.46 (m, 1H) 1.47-1.55 (m, 1H) 1.87-1.96 (m, 1H) 2.43-2.49 (m, 1H) 7.38 (d, 2H) 7.74 (d, 2H) 12.43 (s, 1H).