Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[CH:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10](=[O:28])[CH:9]=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:31][CH2:30][C:29]([OH:33])=[O:32])=[CH:20][CH:19]=1
Reactant: C=CC(=O)OC
Reactant: Cc1ccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc(C=CCC(CCC(=O)O)(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1
Reaction time: 36 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred suspension of 1-(p-chlorophenyl)-4-phenyl-7-(p-methylphenyl)-1,6-heptadien-3-one (14.55 g., 0.038 mole) in glyme (150 ml.) followed by addition of methyl acrylate (3.87 g., 0.045 mole) in glyme (25 ml.). The mixture is warmed slightly to obtain solution then is stirred for 24 to 48 hours. The solvent is removed under reduced pressure and water (1000 ml.) and dilute hydrochloric acid is added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (MgSO4). After removal of the solvent the residue is heated with a solution of 20% sodium hydroxide (20 ml.) in methanol (800 ml.) on the steam bath for 24 hours. The methanol is removed in vacuo and the residue is dissolved in a large volume of water. Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming and dilute hydrochloric acid is added. The solid that separates is collected, washed well with water, and air-dried, yield 10.43 g., m.p. 170°-180°C. Recrystallization from acetonitrile gives material with m.p. 182°-185°C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][CH:3]=1.Cl.ClC1C=CC(C=[N:18][NH:19][C:20](=[NH:23])SC)=CC=1.NN>C(O)C>[NH2:18][NH:19][C:20]([NH:8][NH:7][CH2:6][C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[NH:23]
Reactant: NNCc1ccc(Cl)cc1
Reactant: CSC(=N)NN=Cc1ccc(Cl)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Product: N=C(NN)NNCc1ccc(Cl)cc1

Procedure:
The same compound is synthesized by the reaction of equimolar quantities of p-chlorobenzylhydrazine and methyl-3-(4-chlorobenzylidene)thiocarbazimidate hydrochloride (see Example 10) in hot ethanol. It is also prepared by the reaction of equimolar amounts of 1-(p-chlorobenzyl)-S-methylisothiosemicarbazide and hydrazine in warm ethanol, which affords 1-amino-3-(p-chlorobenzylamino)guanidine, followed by treatment of the latter with an equimolar quantity of p-chlorobenzaldehyde in hot isopropanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]#[C:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][C:28]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:20][CH:19]=2)[CH2:9][O:10][C:11]([CH3:15])([CH3:14])[O:12][CH2:13]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C#Cc2ccc(CCC#CC3(O)CCCCC3)cc2)COC(C)(C)OC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CCc2ccc(CCCCC3(O)CCCCC3)cc2)COC(C)(C)OC1
Yield: 67.5 %

Procedure:
A mixture of the product of Step B (0.07 g, 0.13 mmol), and 10% Pd/C (0.04 g) was stirred for 36 h in EtOH (5 ml) under H2. The catalyst was removed by filtration through Celite pad and the filtrate as evaporated to dryness to give the title product (0.043 g; 60%), as colourless paste. 1H-NMR (CDCl3) 1.35 (s, 9H); 1.39 (s, 3H); 1.41 (s, 3H); 1.48-1.49 (m, 20H); 2.15 (d, 2H, J=11.22 Hz); 2.49-2.45 (m, 2H); 3.64 (d, 2H, J=11.73 Hz); 3.86 (d, 2H, J=11.7 Hz); 3.94 (m, 2H); 4.95 (s, 1H); 6.78 (d, 2H, J=8.58 Hz); 7.04 (d, 2H, J=8.55 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH:3]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>[Cl-].[Na+].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.C(OCC)(=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH:37]=[C:36]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH2:35][CH2:34]1)=[O:32])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c(C2CC(C)(C)CC(C)(C)C2)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: [Cl-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a mixture of trifluoromethanesulfonic acid 4-methyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl ester (430 mg, 1.14 mmol) produced in Example (104d), 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester (421 mg, 1.36 mmol) (Paul R. Eastwood, Tetrahedron Lett., 2000, 41, 3705) and 1,2-dimethoxyethane (20 mL) were added tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.06 mmol) and 2N aqueous solution of sodium carbonate (1.72 mL, 3.41 mmol), followed by stirring for 8 hours at an external temperature of 90° C. under a nitrogen atmosphere. Brine was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated to give a residue, which was purified by silica gel column chromatography (ethyl acetate/heptane) to give 297 mg of the title compound as a light yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt](=O)=O>[CH:1]1([CH2:7][C@@H:8]([OH:12])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](O)Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)[C@H](O)CC1CCCCC1

Procedure:
5 g (30.1 mmole) of 3-phenyl-D-lactic acid [Rf (2)=0.45-0.55] is dissolved in 70 ml of acetic acid and submitted to hydrogenation in the presence of 0.25 g of platinum(IV)oxide catalyst in the temperature range of 40° to 50° C. The reaction is monitored by thin-layer chromatography [final product: Rf (2)=0.6-0.7]. After completed reaction the catalyst is filtered off, the filtrate is evaporated from a water bath at a temperature not higher than 40° C., at 20-25 millibar. Then 20 ml of toluene is evaporated twice from the residue which is finally recrystallized from n-hexane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([C:43]2[CH:57]=[CH:56][C:46]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[CH:45][CH:44]=2)[C@@H:10]([S:25][CH2:26][C:27]2([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[O:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][O:28]2)[C:11](=[O:24])N2[C@@H](C3C=CC=CC=3)COC2=O)=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:24])[C@H:10]([S:25][CH2:26][C:27]3([C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)[O:28][CH2:29][C:30]([CH3:33])([CH3:34])[CH2:31][O:32]3)[C@H:9]2[C:43]2[CH:44]=[CH:45][C:46]([O:47][CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[CH:56][CH:57]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(CS[C@@H](C(=O)N3C(=O)OC[C@@H]3c3ccccc3)[C@@H](Nc3ccc(F)cc3)c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: COc1ccc(C2(CS[C@H]3C(=O)N(c4ccc(F)cc4)[C@@H]3c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 40.8 %

Procedure:
tert-Butyl (4-{(1S,2R)-1-[(4-fluorophenyl)amino]-2-({[2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (2.0 g, 2.5 mmol) was dissolved in dry toluene (200 ml) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 1.8 ml, 7.5 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was cooled to 45° C. and tetrabutylammonium fluoride (TBAF, 150 mg) was added and the mixture was stirred at 45° C. for two hours. The mixture was concentrated under reduced pressure and filtered through a short column of silica (hexane:EtOAc 4:1). Purification of the crude oil by flash-chromatography (hexane:EtOAc 5:1) gave 0.65 g (41%) of the title compound as a yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 3.0-3.2 (m, 2H), 3.3-3.5 (m, 4H), 3.8 (s, 3H), 4.0 (d, 1H), 4.5 (s, 2H), 4.8 (d, 1H), 6.8-7.0 (m, 6H), 7.2-7.4 (m, 6H).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH2:10][CH3:11])=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:2][C:1]([C:4]1[C:9]([CH2:10][CH3:11])=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: BrBr
Reactant: CCc1nccnc1C(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1nccnc1C(=O)CBr
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 2-acetyl-3-ethylpyrazine (1.0 g, 6.66 mmol) in chloroform (15 mL) was added Br2 (0.38 mL, 7.32 mmol, 1.1 eq) dropwise at 0° C. The reaction mixture was stirred at 40° C. for 4 h. The reddish solution turned to dark brown. The reaction mixture was concentrated in vacuo and used in the step 2 without further purification. MS LC-MS (MH+=231)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25]>>[Br:1][C:2]1[C:3]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]1[OH:25])=[O:9]
Reactant: O=C(O)c1cnc(OCCCCCO)c(Br)c1
Reactant: N[C@@H]1CCCC[C@H]1O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCCCCCO)c(Br)c1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 31b, using 5-bromo-6-(5-hydroxy-pentyloxy)-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials to give the product as white solid, MS (ISP): 403.4 (MH+).
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
20 ml of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 27 grams of powdered potassium hydroxide and 59 grams of 1-bromooctadecane were stirred in 250 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 200 ml. The reaction mixture was then cooled to room temperature and stirred at this temperature overnight. 200 ml water was added, the reaction mixture extracted twice with 200 ml diethyl ether, the combined organic phase was washed with 200 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 100 ml of a mixture of 90:10:5 (v/v) methanol:water:concentrated hydrochloric acid, and the resulting solution was refluxed for 1 hour, followed by cooling to room temperature and addition of 200 ml water. The product was extracted twice with 200 ml chloroform, washed consecutively with 200 ml water, 200 ml of a saturated aqueous solution of sodium carbonate, and again with 200 ml water. The solvent was then removed under reduced pressure, and the crude product was crystallized from 500 ml hexane to give 39.5 grams of pure (S)-1-octadecyl-glycerol, which was dried in a desiccator under reduced pressure with phosphorus oxide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][CH2:23][CH2:24][CH2:25]Br>CC(C)=O>[Br:22][CH2:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: N#CC1(c2ccc(O)cc2)CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Temperature: 70 °C
Yield: 86.9 %

Procedure:
1-(4-Hydroxyphenyl)cyclohexanecarbonitrile (2.0 g, 10 mmol) was taken in acetone (150 mL) and then Cs2CO3 (8.1 g, 25 mmol) was added followed by dropwise addition of 1,3 dibromopropane (5.1 mL, 50 mmol). The mixture was heated for 3 h at 70° C. After cooling and filtration, the mixture was concentrated and the residue was purified by flash chromatography (50 g silica gel, DCM) to provide the title compound (2.8 g, 87%). Note: presence of allyl derivative as impurity.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:15]([CH2:17][NH2:18])[OH:16]>>[OH:16][CH2:15][CH2:17][NH:18][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: NCCO
Product: OCCNc1nc2ccccc2n2ccnc12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with ethanolamine according to a procedure that is similar to that followed in example 3 there is obtained 4-(2-hydroxyethylamino)imidazo[1,2-a]quinoxaline. m.p. (DSC)=150.8° C. (onset); IR (KBr): 3312, 1598, 1564 cm-1 ; 1H-NMR (CDCl3 /CD3OD): δ8.2 (1H,s), 8.1÷7.55 (2H,m), 7.55 (1H,s), 7.4÷7.2 (2H,m), 3.8 (4H,s); UV (EtOH): λmax =227, 285, 297, 317, 330 nm. Elementary analysis for C12H12N4 (m.w. 228.25): calcd. C 63.14, H 5.30, N 24.55%; found C 63.16, H 5.40, N 24.99%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@H:5]([C@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.C(OC(C)C)(=O)[C@@H](CC(OC(C)C)=O)O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.[CH3:56][O:57][C:58]1[CH:63]=[CH:62][C:61]([N:64]2[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]2)=[CH:60][CH:59]=1>C(Cl)Cl>[CH3:56][O:57][C:58]1[CH:59]=[CH:60][C:61]([N:64]2[CH2:69][CH2:68][N:67]([C:8]([C@H:7]([C@H:5]3[O:6][C:2]([CH3:1])([CH3:16])[O:3][C:4]3=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:66][CH2:65]2)=[CH:62][CH:63]=1
Reactant: CC(C)C[C@H](C(=O)O)[C@H]1OC(C)(C)OC1=O
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(C)OC(=O)C[C@@H](O)C(=O)OC(C)C
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@H]3OC(C)(C)OC3=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a cold solution (0° C.) of (2S)-2-[(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (prepared according to WO 94/02447 or similarly to Seebach et al., 1990, Org Syntheses, Coll. Vol. III, p 153-159 but starting from diisopropyl (R)-(+)-malate, 150 mg, 0.65 mmol) in anhydrous DCM (3 mL) were added DIEA (115 μL, 0.69 mmol) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (190 mg, 0.72 mmol, Aldrich). The reaction mixture was stirred at 0° C. for 40 min. Then a solution of 1-(4-methoxyphenyl)-piperazine (138 mg, 0.72 mmol, Chess) and DIEA (115 μL, 0.69 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture was stirred for 1 hour at RT and then poured on a silica column (30 g, wet with c-Hex/EtOAc 4:1). Purification was performed with a gradient cHex/EtOAc 4:1 to c-Hex/EtOAc 1:1 in 30 min to give 158 mg of a white powder. Recrystallization from iPrOH gave 112 mg (43%) of the title compound as a white powder. HPLC, Rt: 3.02 min (purity: 99.0%). LC/MS, M+(ESI): 405.3. 1H NMR (CD3OD, 300 MHz) δ 7.00 (d, J=9.2 Hz, 2H), 6.89 (d, J=9.2 Hz, 2H), 4.56 (d, J=8.7 Hz, 1H), 3.87 (m, 3H), 3.78 (s, 3H), 3.73 (m, 1H), 3.50 (m, 1H), 3.15-3.00 (m, 4H), 1.93-1.72 (m, 2H), 1.66 (s, 3H), 1.58 (m, 1H), 1.56 (s, 3H), 0.98 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH:27]=O)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.CO>[CH2:29]([NH:36][CH2:27][CH2:26][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[C:12]([C:17]2([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:19][CH2:18]2)[N:11]=3)=[C:2]([F:1])[CH:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: O=CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Fc1cc(CCNCc2ccccc2)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Reaction time: 72 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)acetaldehyde (44 mg, 0.113 mmol) was dissolved in chloroform (1.1 mL) before it was stirred at ambient temperature with benzylamine (62 μl, 0.57 mmol) and PTSA (1 mg) for 16 h. Methanol (1.1 mL) and sodium cyanoborohydride (7.1 mg, 0.113 mmol) were then added and allowed to stir in the reaction mixture over 3 d. The reaction mixture was diluted with DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed with sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after flash chromatography. MS (ESI) m/z: Calculated: 479.2; Observed: 480.1 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:1][C:2]2[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[O:21])=[CH:23][CH:24]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cccc(S(=O)(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 3-amino benzenesulfonic acid (1.7 g, 10 mmol) in pyridine (100 mL) was added 4-tert-butyl benzoyl chloride (2.0 mL, 10 mmol). The reaction was stirred at room temperature 16 h and the solvent was evaporated under vacuum. The residue was dissolved in EtOAc and washed with 1 M aqueous hydrochloric acid. The aqueous washes were extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (10%-20% MeOH—CH2Cl2) to obtain 3-(4-tert-butylbenzamido)benzenesulfonic acid (2.1 g, 63% yield). LC/MS: m/z 334.3 (M+H)+ at 2.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[C:35]1([CH3:50])[CH:40]=[CH:39][C:38]([S:41]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)=O)=[CH:37][CH:36]=1.[C:51]12([CH2:61][S:62]([O-:65])(=[O:64])=[O:63])[C:58]([CH3:60])([CH3:59])[CH:55]([CH2:56][CH2:57]1)[CH2:54][C:52]2=[O:53].[NH4+]>>[C:51]12([CH2:61][S:62]([O-:65])(=[O:63])=[O:64])[C:58]([CH3:60])([CH3:59])[CH:55]([CH2:56][CH2:57]1)[CH2:54][C:52]2=[O:53].[C:46]1([CH3:49])[CH:45]=[CH:44][C:43]([S+:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:50])=[CH:36][CH:37]=2)[C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:34][CH:33]=2)=[CH:48][CH:47]=1
Reactant: Cc1ccc(S(=O)c2ccc(C)cc2)cc1
Reactant: CCCCCCCCOc1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCCCCCCCOc1ccc([S+](c2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 3-neck flask equipped with a thermometer, a nitrogen outlet and a mechanical stirrer, was charged with phosphorous pentoxide (8.64 g) followed by methanesulfonic acid (85.20 g). The resulting mixture was stirred at room temperature for 0.5 hour and then heated at 50° C. for 2-3 hours to obtain a homogeneous suspension. The mixture was cooled to below 10° C. in an ice-water bath and n-octylphenyl ether (21.66 g, 0.105 mol) was added. Next, p-tolylsulfoxide (20.03 g, 0.10 mol) was added with good stirring while maintaining the temperature of the reaction below 10° C. After stirring for 1 hour, the cooling bath was removed and the reaction was stirred at room temperature for 16 hours. Thereafter, the reaction mixture was added dropwise to a mixture of ice-water (500 mL) with vigorous stirring. The aqueous mixture was washed with toluene/hexane (3×100 mL, 1:1) and extracted with dichloromethane (3×200 mL). The combined organic layers were treated with an aqueous solution of ammonium 10-camphorsulfonate (prepared by neutralization of 10-camphorsulfonic acid (29.04 g, 0.125 mol) with ammonium hydroxide (14.53M, 8.6 mL, 0.125 mol)). The two phase solution was stirred at room temperature for 16 hours. The layers were separated and the aqueous phase extracted with dichloromethane (3×200 mL). The combined organic layers were washed with water (3×200 mL) and concentrated in vacuo to give a dark oil which solidified on standing to give a lightly colored solid @ 65 g. The solid was triturated in ether-ethylacetate for 18 hours, collected by suction filtration and dried in vacuo to provide the title compound, di-(4-tolyl)-4-octyloxyphenylsulfonium 10-camphorsulfonate, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.[N+]([O-])(O)=O.[CH3:23][N:24]([CH3:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[CH:27][CH:26]=1.[OH-].[Na+]>COCCO>[CH3:23][N:24]([CH3:35])[C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]2[N:34]=[CH:12][C:9]3[CH2:8][CH2:7][C:5]4[N:6]=[C:2]([CH3:1])[S:3][C:4]=4[C:10]=3[N:33]=2)=[CH:29][CH:30]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: CN(C)c1ccc(NC(=N)N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: COCCO
Product: Cc1nc2c(s1)-c1nc(Nc3ccc(N(C)C)cc3)ncc1CC2
Temperature: 100 °C
Yield: 9.2 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (119 mg, 4.5 mmol), N-(4-dimethylamino-phenyl)-guanidine nitrate (137 mg, 4.5 mmol), NaOH (18 mg, 4.5 mmol), and 2-methoxyethanol (2 mL) was heated at 100° C. for 5 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (20% EtOAc:hexane) gave the title product as a dark yellow solid (140 mg, 92%): mp 176-177° C. Anal. RP-HPLC: tR 11.9 min (0-60% MeCN, purity 100%). 1H-NMR (DMSO-d6): δ 9.23 (s, 1H, NH), 8.28 (s, 1H, Py-H), 7.60 (d, 2H, J 9.2, Ph-H), 6.75 (d, 2H, J 9.2, Ph-H), 3.02 (m, 4H, CH2—CH2), 2.88 (s, 6H, NMe2), 2.75 (s, 3H, CH3). 13C-NMR (DMSO-d6): δ 168.90, 159.67, 159.08, 155.77, 146.32, 131.16, 120.65, 115.25, 113.32, 41.14, 25.15, 23.45, 19.79. MS (ESI+): m/z 338.10 (M+H)+.