Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](N)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1.ClC(Cl)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Reactant: COc1ccc(CNC(=O)CNc2cccc(Cl)c2C)cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
200 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)glycinamide was dissolved in 2.0 mL of pyridine, and a solution (2.0 mL) of 200 mg of 4-hydroxybenzenesulfonamide in dichloroethane was added thereto, followed by stirring at 80° C. overnight. The reaction liquid was concentrated under reduced pressure, to the residue was added water, followed by extraction with ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70), and further purified by silica gel column chromatography (chloroform:methanol=100:0 to 97:3), and the obtained residue was crystallized from diisopropyl ether to obtain 68 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-hydroxyphenyl)sulfonyl]-N-(4-methoxybenzyl)glycinamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=4)[CH:19]=[O:20])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:25]([Mg]Br)#[C:26][CH3:27]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:24]=[C:11]3[CH:12]=[C:13]([C:16]4[CH:17]=[C:18]([CH:19]([OH:20])[C:25]#[C:26][CH3:27])[CH:21]=[CH:22][CH:23]=4)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Reactant: CC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(O)c1cccc(-c2ccn3nc(-c4ccc(F)cc4)cc3c2)c1
Yield: 67.9 %

Procedure:
The procedure described in stage 2.5 is followed, starting with 0.300 g (0.95 mmol) of 3-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl]benzaldehyde obtained according to the process described in 2.4, in solution in 10 ml of tetrahydrofuran, followed by addition of 5.70 ml (2.85 mmol) of a (propyn-1-yl)magnesium bromide solution (0.5M in tetrahydrofuran) and after chromatography on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (8/2), 0.23 g (67%) of the expected product is obtained in the form of a pale yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[N:13]=[CH:14][C:15]3[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]2=O.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>CO>[C:24]([O:28][N:29]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][C:7]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)ON
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Yield: 75.9 %

Procedure:
6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime was prepared using the method D (step 1) illustrated in example 1B. 6-bromo-2-isoquinolin-3-yl-chromen-4-one (600 mg, 1.7 mmol) was treated with O-tert-butyl-hydroxylamine hydrochloride (427 mg, 3.4 mmol) in methanol (10 ml) under microwave irradiation to yield 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (546 mg, 76%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C-]#N.[Na+].C[C:17](O)=[O:18]>CO.O=[Mn]=O>[CH2:1]([C:5]1[NH:6][C:7]([C:11]([O:18][CH3:17])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-Butyl-4-chloro-5-formylimidazole (4.9 g, 26 mMol) in methanol (350 ml) were added NaCN (12.98 g, 0.26 Mol), glacial AcOH (2.5 ml) and MnO2 (57.6 g, 0.663 Mol), and the mixture was stirred at room temperature for 72 h. The reaction was filtered through a pad of celite and concentrated in vacuo. The residue obtained was partitioned between EtOAc (150 ml) and water (50 ml), and the organic phase was washed with brine and then dried over sodium sulfate. The crude product (5.73 g), obtained after removal of the solvent under reduced pressure, was purified by flash-chromatography on silica-gel using EtOAc-hexane (1:5). Yield 4.5 g (80%, white solid). The product was crystallized from ethylacetate-hexane to give fine needles.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH:10]([C:6]1[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Cl)c(Nc2ccccc2)n1

Procedure:
A solution of 2,4,5-trichloropyrimidine (Method 8; 5.5 g, 30.0 mmol), aniline (2.79 g, 30.0 mmol) and N,N-diisopropylethylamine (3.87 g, 30.0 mmol) in n-butanol (75 ml) was heated under reflux for 4 hours. Volatile material was removed by evaporation and the residue was dissolved in DCM (100 ml). The solution was washed with water (3×100 ml) and saturated brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified by column chromatography on silica gel, eluting with 15% ethyl acetate/isohexane, to give the product as an oil which solidified on standing (3.94 g, 54%). NMR: 7.2 (t, 1H), 7.4 (t, 2H), 7.6 (d, 2H), 8.4 (s, 1H), 9.45 (br s, 1H); MS (MH+): 240, 242, 244.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C1COCC1.CN(C=O)C.C(NC(C)C)(C)C.[CH3:44][C:45]([OH:49])([C:47]#[CH:48])[CH3:46]>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.[Cu]I>[NH2:20][C:17]1[O:18][CH2:19][C@:15]2([C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:48]#[C:47][C:45]([CH3:46])([OH:49])[CH3:44])[CH:3]=3)[O:8][C:9]3[C:14]2=[CH:13][C:12]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:11][CH:10]=3)[N:16]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 110 °C

Procedure:
Combined (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (99 mg, 0.242 mmol), tetrakis(triphenylphosphine)palladium (28.0 mg, 0.024 mmol), copper(i) iodide (4.61 mg, 0.024 mmol) and THF (969 μL, 0.242 mmol) and DMF (969 μL, 0.242 mmol). Added diisopropylamine (679 μL, 4.85 mmol) then 2-methylbut-3-yn-2-ol (118 μL, 1.211 mmol) and flushed the reaction tube with argon. Sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH to give (S)-4-(2′-amino-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol as a white solid after evaporation from DCM/hexane.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@H:8]([CH2:18][CH3:19])[CH2:9][C@:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C@@H:8]([CH2:18][CH3:19])[CH2:9][C@@:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH:11]=[N:22][C:23]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]3[C:24]=2[CH:25]=[N:26][C:27]([CH3:34])=[N:28]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncc2c(N)ccc(F)c2n1
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CC[C@@H](C[C@@](O)(C=Nc1ccc(F)c2nc(C)ncc12)C(F)(F)F)c1cccc(F)c1OC

Procedure:
In the same way as in Example 31, 123 mg (0.40 mmol) of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 72 mg (0.60 mmol) of 5-amino-8-fluoro-2-methylquinazoline and 0.22 ml of titanium tetraethoxide are reacted to give (2R*,4S*)-4-(3-fluoro-2-methoxyphenyl)-1-[(8-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 170 mg of crude imine are cyclized in the same way as in Example 31 at −30° C. with 2.8 ml (2.8 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (dichloromethane/ethyl acetate 0-40%) gives 68 mg of product.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C=O)C.O>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a suspension of dimethyl malonate (9.77 mL, 85.07 mmol, 1.2 eq) in DMF (100 mL) and K2CO3 (29.36 g, 212.76 mmol, 3.0 eq) was added 1-fluoro-4-nitrobenzene (7.51 mL, 70.91 mmol, 1.0 eq) at RT and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled to RT and diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate layers were collected, washed with cold water (2×50 mL), brine (50 mL), dried over sodium sulfate and evaporated under vacuum. The crude product was washed with n-pentane (50 mL) to get dimethyl 2-(4-nitrophenyl)malonate 14 g, 78%) as pale yellow solid (TLC system: EtOAc/PE (3:7), Rf: 0.50).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:32]=[N:33][CH:34]=1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncc(F)c1
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1) and (5-fluoropyridin-3-yl)boronic acid to afford a yellow crystals. UPLC-MS (Condition 3) tR=1.08 min, m/z=479.4 [M+H]+, m/z=477.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=11.29 Hz, 1H) 3.15-3.30 (m, 2H) 3.35-3.46 (m, 1H) 4.16-4.24 (m, 1H) 4.89 (d, J=3.39 Hz, 1H) 7.69 (d, J=8.66 Hz, 2H) 7.84 (dt, J=9.72, 2.16 Hz, 1H) 7.89-7.95 (m, 2H) 8.08 (d, J=2.38 Hz, 1H) 8.51 (s, 1H) 8.60 (d, J=2.64 Hz, 1H) 8.78 (d, J=2.26 Hz, 1H) 10.29 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:17](=[O:18])[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:30])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-phenyl-piperidine-1,4-dicarboxylic acid monobenzyl ester (3.39 g, 10 mmol) and SOCl2 (7 mL, 100 mmol) in CHCl3 (150 mL) is heated at reflux for 3 h. The solvent and excess SOCl2 are evaporated into a cold trap and the residue is redissolved in CHCl3 (50 mL). The solution is added to a solution of methylbenzylamine (1.45 g, 12 mmol) and DIPEA (2 mL, 12 mmol) in cold (0° C.) CHCl3 (100 mL). The mixture is stirred for 15 h at r.t. and then quenched with sat. aq. Na2CO3 (50 mL). The phases are separated and the aq. phase is extracted with CH2Cl2 (2×50 mL). The combined organic extracts are washed with 1N aq. HCl (50 mL) and sat. aq. NaCl (50 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by FC (SiO2, heptane-EtOAc) to provide the title compound.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[F-].[Cs+].C([O-])(O)=O.[Na+]>COCCOC.O>[F:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:11][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[C:2]([C:27]3[CH:28]=[N:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:10][C:9]=12
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 80 °C
Yield: 32.6 %

Procedure:
A mixture of the nitro compound 42 (500 mg, 1.36 mmol), 6-methoxypyridin-3-ylboronic acid (312 mg, 2.04 mmol) and CsF (620 mg, 4.08 mmol) were suspended in DME (12 ml) and NaHCO3 (342 mg, 4.08 mmol), dissolved in the minimum amount of water, was added. The mixture was de-aerated by bubbling N2 through the solution for 10 min, heated at 80° C. for 3 hrs and concentrated to dryness. The formed residue was dissolved in DCM and washed with water. The DCM was collected, dried over sodium sulfate, filtered and the DCM was removed by evaporation. The resultant solid was triturated with Et2O to afford the title compound 45 (176 mg, 32% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (m, 1H), 8.56 (m 1H), 8.46 (m, 1H), 8.22 (m, 2H), 8.01 (s, 1H), 7.72 (t, J=8.6 Hz, 1H), 6.99 (d, J=5.47 Hz, 1H), 6.90 (m, 1H), 3.97 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CN.C(C1NC=CN=1)([C:15]1[NH:16]C=CN=1)=O>>[CH3:15][NH:16][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CN
Product: CNC(=O)c1cccc(Br)n1

Procedure:
6-Bromopicolinic acid (Aldrich) was coupled with methyl amine using carbonyl diimidazole (CDI) as coupling reagent to afford 6-bromopyridine-2-carboxylic acid methylamide. The 6-bromopyridine-2-carboxylic acid methylamide underwent Suzuki coupling with 4-phenoxyphenylboronic acid, in the presence of tetrakis(triphenylphosphine)palladium as catalyst to give 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide as a solid. 1H NMR (CDCl3): δ 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.90 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.38 (t, J=8.4 Hz, 2H), 7.18-7.06 (m, 5H), 3.08 (d, J=5.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([O:10]CC2C=CC=CC=2)=[C:5]([CH3:18])[N:4]=1.[OH-].[K+].C(O)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:18])[C:6]([OH:10])=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)c(OCc2ccccc2)c(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(C)c(O)c(C)n1

Procedure:
The 2-methoxy-4,6-dimethyl-5-benzyloxy pyrimidine 0.7 g (2.7 mmol) is dissolved in 10 ml of ethanol with 0.3 g (5.4 mmol) of KOH. The whole is refluxed for 11 hours, and after cooling the reaction is diluted with 20 ml of water and brought to pH 5 with glacial acetic acid. The mixture is extracted into ethyl acetate (3×25 ml), dried over Na2SO4 and stripped in vacuo. The resulting solid is purified by column chromatography on silica gel using 9:1 hexane:ethyl acetate as eluent. The yield is 0.4 g (98%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=[C:4]([CH3:16])[C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].CCN(CC)CC.[O:29](S(C(F)(F)F)(=O)=O)[S:30]([C:33]([F:36])([F:35])[F:34])(=O)=[O:31]>ClCCl>[CH3:16][C:4]1[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:2]([O:1][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:31])=[O:29])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:15])[C:6]=2[N:5]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(C)nc2c(c1O)c1ccccc1n2C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(C)nc2c(c1OS(=O)(=O)C(F)(F)F)c1ccccc1n2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
An ice cold mixture of ethyl 4-hydroxy-2,9-dimethyl-9H-pyrido[2,3-b]indole-3-carboxylate (210 mg, 0.739 mmol) in dichloromethane (DCM) (3.5 mL) was treated with Et3N (0.154 mL, 1.108 mmol) and Tf2O (0.137 mL, 0.812 mmol), and then stirred at 0° C. for 90 min. The mixture was concentrated and purified with column chromatography (0-100% DCM/Hexane) to afford ethyl 2,9-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-9H-pyrido[2,3-b]indole-3-carboxylate (286.8 mg, 0.689 mmol, 93% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.23 (d, J=7.9 Hz, 1 H), 7.65-7.57 (m, 1 H), 7.49 (d, J=8.2 Hz, 1 H), 7.42-7.34 (m, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 3.98 (s, 3 H), 2.88 (s, 3 H), 1.45 (t, 3 H); LCMS (m/z) ES+=417 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.O=S(Cl)Cl.CC[N:17](CC)CC.N>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:17])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: N
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 343.9 %

Procedure:
To a solution of 4-chloropicolinic acid (100 mg, 0.64 mmol) in DCM (10 mL) was added one drop DMF and SOCl2 (0.14 mL, 1.92 mmol). The reaction was stirred at rt overnight, then concentrated in vacuo. The resulted residue was dissolved in THF (10 mL), followed by the addition of Et3N (0.2 mL, 0.13 mmol). The mixture was stirred in an ammonia gas atmosphere for 1 hour, then concentrated in vacuo, diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=5/1) to give the title compound as a yellow solid (70 mg 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][S:16][C:15](=S)[S:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[I:19][C:20]1[C:21]([OH:30])=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([CH:27]=1)C=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:30][C:21]1[C:20]([I:19])=[CH:27][C:24]([C@H:15]2[S:14][C@H:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][S:16]2)=[CH:23][C:22]=1[O:28][CH3:29]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(I)c1O

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (32) (FIG. 26) (0.500 g, 1.92 mmole), 5-iodovanillin (0.411 g, 1.48 mmole), pyridinium para-toluenesulfonate (0.193 g, 0.769 mmole) and 50 ml dry benzene were refluxed under an argon atmosphere with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer was washed with 3×30 ml H2O and was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.3 cis/trans ratio (0.578 g, 75%) after one crystallization from methanol. The trans isomer (50 mg) was isolated after one additional crytallization from ethanol.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)=O.[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][C:25]=1[CH3:36])(=[O:22])=[O:21]>C(O)C>[CH3:19][S:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:12][CH:13]=3)[CH2:32][CH2:31]2)=[CH:26][C:25]=1[CH3:36])(=[O:21])=[O:22]
Reactant: Cc1cc(N2CCNCC2)ccc1NS(C)(=O)=O
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Solvent: CCO
Product: Cc1cc(N2CCN(CCc3ccc(NS(C)(=O)=O)cc3)CC2)ccc1NS(C)(=O)=O

Procedure:
4-Methanesulphonamidophenethyl methanesulphonate (1.47 g) and 1-(4-methanesulphonamido-3-methylphenyl)piperazine 1/4 hydrate (1.37 g) in ethanol (15 ml) were refluxed overnight, evaporated to dryness, and partitioned between ethyl acetate and water. The title compound (0.2 g) was filtered from the 2-phase mixture and recrystallised from methanol/acetone, yield 0.128 g, m.p. 235°-7°.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:13][CH:11]1[CH2:12][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10]1)(=[O:27])=[O:26]
Reactant: OC1CC(OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC(OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A 100-mL round-bottom flask was charged with 3-(benzyloxy)cyclobutanol (1.83 g, 10.3 mmol), dichloromethane (20 mL) and triethylamine (2.15 mL, 15.4 mmol), and the solution was cooled to 0° C. Methanesulfonyl chloride (1.20 mL, 1.77 g, 15.4 mmol) was added dropwise, and the resulting solution stirred for 30 min at 0° C. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to afford 3-(benzyloxy)cyclobutyl methanesulfonate (2.60 g, 99%) as a light yellow solid. MS (ESI, pos. ion) m/z 257 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.[OH-].[K+].[C:14]([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20]Br)(=[O:16])[CH3:15].O>CS(C)=O.C(Cl)(Cl)Cl>[C:14]([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)(=[O:16])[CH3:15]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: CC(=O)OCC(C)(C)CBr
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)OCC(C)(C)Cn1cnc(-c2cccnc2)c1
Temperature: 70 °C

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (50 mg) in DMSO (methyl sulfoxide) (1.7 mL) was added powered KOH (57 mg) and 3-bromo-2,2-dimethylpropyl acetate and the resulting suspension was heated at 70° C. for 48 hours. Water was added followed by CHCl3, the aqueous layer was extracted with CHCl3, the combined organic layers were washed with brine, dired over Na2SO4 and evaporated in vacuo. The redisue was purified by preparative TLC (10% MeOH-90% CH2Cl2) the title compound as slightly yellow oil.