Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[NH:8][CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[CH3:17][C:18]([CH3:21])([O-])[CH3:19].[Na+].BrCC1CC1>CS(C)=O>[Cl:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[N:8]([CH2:17][CH:18]3[CH2:21][CH2:19]3)[CH2:7][CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc(Cl)nc2c1NCC1COCCN21
Reactant: CC(C)(C)[O-]
Agent: BrCC1CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1N(CC1CC1)CC1COCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.4 %

Procedure:
To a round-bottom flask was added 2-chloro-4-methyl-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x20, 248 mg, 1.030 mmol) in DMSO (4 mL). Sodium tert-butoxide (119 mg, 1.236 mmol) was added, followed by (bromomethyl)cyclopropane (0.105 mL, 1.082 mmol), and the reaction mixture was stirred overnight at room temperature. The mixture was subsequently filtered and the filtrate was purified by preparatory HPLC using a gradient of 25-50% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a brown solid (56 mg, 0.190 mmol, 18%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O, 295.12; found 295.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33]O)[CH:29]=2)[CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:33][CH2:32][O:31][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][CH:22]=[N:21]3)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1ccc2cccnc2c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCOc2ccc3cccnc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.267 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.305 g), stirred for 15 minutes and treated with the mesylate prepared from 1.135 g of 2-(7quinolyloxy)ethanol. The mixture was heated under argon at 60° C. for 5 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were washed with water, dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) and crystallized from dichloromethane-hexane to provide 0.93 g of alpha-oxo-4-[[2-(7-quinolyloxy)ethyl]oxy]benzeneacetic acid methyl ester as a colorless solid, mp 92°-94° C.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=2)[C:20]([F:23])([F:22])[F:21])[CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5].[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:10]1[CH2:11][CH2:12][CH:7]([NH:6][C:4](=[O:5])[C:3]2[CH:13]=[CH:14][C:15](/[CH:17]=[CH:18]/[CH:19]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)[C:20]([F:23])([F:21])[F:22])=[CH:16][C:2]=2[Br:1])[CH2:8][CH2:9]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Br
Solvent: ClCCl
Product: CC(=O)N1CCC(NC(=O)c2ccc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)cc2Br)CC1
Reaction time: 0.17 h
Yield: 55.1 %

Procedure:
To a stirred solution of (E)-2-bromo-N-(piperidin-4-yl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzamide (0.1 g, 0.16 mmol) in CH2Cl2 (10.0 mL) was added TEA (0.046 mL, 0.35 mmol) and stirred for 10 min. Then acetyl chloride (0.014, 0.18 mmol) was added and stirred for 16 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution and brine solution. The combined CH2Cl2 layer was dried over Na2SO4 and concentrated under reduced pressure to afford crude compound. The crude compound was washed with 5% Et2O/n-pentane to afford the title compound as a white solid (0.054 g, 50%).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1>ClCCl>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:30])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:27]([CH3:29])[CH3:28])[CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(=O)Cc2cccc(O[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Solvent: ClCCl
Product: CC(C)[Si](Oc1cccc(CC(=O)c2ccc(O)cc2)c1)(C(C)C)C(C)C
Reaction time: 4 h

Procedure:
To a stirred solution of 40.7 g (0.095 mol) of 4′-methoxymethyloxy-2-(3-triisopropylsilyloxy-phenyl)-acetophenone (5c), from Example 5, in 400 mL of dichloromethane at 0° C. was added all at once 37.5 g (0.099 mol) of solid trimethylammoniumphenyl perbromide. The ice-water bath was removed and the reaction mixture was stirred further for 4 h under an inert atmosphere of nitrogen. The reaction mixture was partitioned between ethyl acetate, ice, brine, 5% aqueous sodium thiosulfate, and saturated sodium bicarbonate. The organic phase was separated washed with brine; dried over anhydrous sodium sulfate, filtered, evaporated, and dried in vacuo to give the crude product which was used without further purification. 1H 500 MHz NMR(CDCl3) ppm(δ): 1.07 (d, 18H), 1.2 (m, 3H), and 6.3 (s, 1H).
Reaction SMILES: [ClH:1].[O:2](CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:3]1C=CC=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.O[C@H](COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C2C(=CC=CC=2)C=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:113][CH:114]([CH2:129][O:130][C:131]1[CH:136]=[CH:135][C:134]([O:137][CH3:138])=[CH:133][CH:132]=1)[CH2:115][NH:116][C:117]([CH3:128])([CH3:127])[CH2:118][C:119]1[CH:124]=[CH:123][C:122]([O:125][CH3:126])=[CH:121][CH:120]=1>>[ClH:1].[OH:113][CH:114]([CH2:129][O:130][C:131]1[CH:136]=[CH:135][C:134]([O:137][CH3:138])=[C:133]([O:2][CH3:3])[CH:132]=1)[CH2:115][NH:116][C:117]([CH3:128])([CH3:127])[CH2:118][C:119]1[CH:120]=[CH:121][C:122]([O:125][CH3:126])=[CH:123][CH:124]=1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)c(OC)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 390 (M+, 0.0), 269 (17), 268 (100), 163 (6), 153 (5), 121 (21), 114 (17), 77 (5), 71 (19), 70 (17), 58 (7).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][C:21](=O)[C:15]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]>O1CCCC1>[CH2:7]([C:9]1[C:17]2[N:16]3[C@H:18]([CH3:23])[CH2:19][NH:20][CH2:21][C:15]3=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH3:8]
Reactant: CCc1cccc2cc3n(c12)[C@H](C)CNC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cccc2cc3n(c12)[C@H](C)CNC3
Yield: 100 %

Procedure:
Lithium aluminium hydride (532 mg) was added in portions to a solution of (R)-6-ethyl-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (800 mg, 3.50 mmol) in tetrahydrofuran (30 mL) and the resulting suspension was heated to reflux for 1 h. After cooling the reaction was quenched by careful addition of 1 M aqueous sodium potassium tartrate solution (50 mL). Then methanol (50 mL) and ethyl acetate (50 mL) were added, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated to yield the title compound (750 mg, 100%). White solid. ISP-MS: m/e=215.3 ([M+H]+).
Reaction SMILES: C(O)C.CNC.C([Li])CCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(Br)(Br)(Br)[Br:21]>O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([Br:21])[CH:15]=1
Reactant: COc1ccncc1
Reactant: BrC(Br)(Br)Br
Agent: CNC
Agent: [Li]CCCC
Solvent: O
Solvent: CCO
Product: COc1ccnc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N,N-dimethylamine ethanol (78.086 g, 0.876 mole) in anhydrous hexanes(1241 mL.) was cooled to 0° C. and butyllithium (2M soln. 876 mL., 1.757 mole) was added by use of an addition funnel. After 30 minutes at 0° C., 4-methoxypyridine(47.87 g, 0.438 mole) was added. Stirring continued at 0° C. for one hour before the reaction mixture was cooled to −78° C. and a solution of CBr4 (363 g, 1.093 mole) was added. The reaction temperature was maintained at 0° C. for 2.5 hours. The water was then added to quench the reaction. The aqueous layer was then separated and extracted with methylene chloride. The organic extractions were washed with brine, dried over magnesium sulfate and evaporated to give crude product. The crude product was purified by column chromatography using 80/20 ethyl acetate/hexanes as the eluants. The purified product was collected and concentrated to give 4-methoxy-2-bromopyridine (17 g. 22% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([OH:17])=O)=[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:27][C:28]1[S:29][CH2:30][CH2:31][N:32]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:15]([N:32]2[CH2:31][CH2:30][S:29][C:28]2=[S:27])=[O:17])=[C:10]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(OCc2ccccc2)c(=O)n1Cc1ccccc1
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(=O)n1Cc1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
1-benzyl-3-benzyloxy-4-carboxy-6-methyl-2(1H)-pyridinone (5.36 g, 15.3 mmol) was dissolved in CH2Cl2 (100 ml) under an atmosphere of nitrogen. Then 2-mercaptothiazoline (1.88 g, 16.1 mmol) and dimethylaminopyridine (DMAP, 0.16 g, 1.0 mmol) were added and the solution stirred for 1 h. Dicyclohexylcarbodiimide (DCC, 3.45 g, 16.9 mmol) was then added in small portions and the reaction mixture stirred for 16 h, and then allowed to stand for 24 h at 0° C. The reaction mixture was filtered and the solvent removed by evaporation. EtOAc (10 ml) was added, and the solution filtered. This last step was repeated 3 times in order to remove the dicyclohexylurea (DCU), yielding a yellow oil. The product was purified by flash column chromatography (silica, CH2Cl2 as eluent). The solvents were removed by rotary evaporation, yielding a viscous yellow oil, which was recrystallized from acetone to give a yellow crystalline solid (Yield: 5.10 g, 74%). 1H NMR (CDCl3, 400 MHz): δ=7.12-7.49 (m, 10H, Bn), 5.98 (s, 1H, HOPO), 5.38 (s, 2H, Bn-CH2), 5.34 (s, 2H, Bn-CH2), 4.59 (t, J=7.3 Hz, 2H, thiaz), 2.90 (t, 2H, J=7.3 Hz, thiaz), 2.27 (s, 3H, HOPO CH3) ppm. Anal. Calcd (Found) for C24H22N2O3S2: C, 63.98 (64.04); H, 4.92 (5.02); N, 6.22 (6.03). FAB-MS (+): m/z: 451 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH3-]C#N.[Na+].C(O)(=O)C>ClCCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(I)cc2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Ic1ccc(C2(CN3CCOCC3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(4-iodophenyl)cyclopropanecarbaldehyde (7 g, 0.025 mol) in 1,2-Dichloroethane (100 mL) is added morpholine (4.5 mL, 0.051 mol) in drops at 0° C. . After 10 min, NaBH3CN (3.2 g, 30 mmol) is added in a portion wise fashion at 0° C. followed by acetic acid (500 μL). The reaction mixture is stirred for another 1 h at same temperature and then at Rt for 10 h. After this time, the reaction mixture is quenched with 10% sodium bicarbonate and extracted with EtOAc. The combined organic layer is washed with water, brine, dried over sodium sulphate and evaporated. The crude product is purified by column chromatography (pet ether and EtOAc) to afford the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.60-7.56 (m, 2H), 7.13-7.08 (m, 2H), 3.47-3.43 (m, 4H), 2.50-2.46 (m, 2H), 2.34 (bs, 4H) 0.0.80-0.77 (m, 2H),0.72-00.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=O)=[CH:18][CH:19]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(C)nc1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(C=Cc2ccc(OC)cc2)nc1

Procedure:
The starting material was prepared by refluxing for 72 hours a mixture of methyl 6-methylnicotinate (60.4 g.), anisaldehyde (163.3 g.), acetic anhydride (120 ml.) and xylene (320 ml.). Steam distillation was used to remove the excess anisaldehyde, the acetic acid formed during the reaction and xylene. The residue was dried in the cold, washed with ether, and dried at 60° C. for 12 hours to give methyl 6-p-methoxystyrylnicotinate, m.p. 170° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[O-:32][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([OH:32])=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-formylphenyl)-L-phenylalanine methyl ester (104 mg) was dissolved in acetone (700 μL) by warming up to about 40° C. A warm (40° C.) solution of KMnO4 (61.2 mg) in a mixture of acetone (900 μL) and water (130 μL) was then added over a 1 h period and the resulting mixture was stirred at that temperature for an additional 2 h. The mixture was filtered through Celite and washed with acetone. The filtrate was taken up with water and acidified to approximately pH 2 with 1N HCl, and extracted with EtOAc. The combined extracts were dried (MgSO4) and evaporated. The residue was purified through a silica gel column using toluene then a gradient of toluene/EtOAc (20:1 to 3:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (85.0 mg). ESMS: m/z 472 (MH+).
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:15]1([C:2]2[N:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cc2c(cn1)sc1ccccc12
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc3c(cn2)sc2ccccc23)cc1
Yield: 26.9 %

Procedure:
2-chloro-3-azadibenzothiophene (1.3 g, 5.7 mmol), phenylboronic acid (0.87 g, 7.1 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.09 g, 0.23 mmol), and potassium phosphate (3.3 g, 14.3 mmol) were mixed in 60 mL of toluene and 6 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.05 g, 0.05 mmol) and the mixture was heated to reflux under nitrogen for 3 days. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 5% ethyl acetate/hexanes. 0.4 g of desired product was obtained after purification.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[C:10]=2[CH3:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:16])=[O:17])=[C:11]([F:36])[C:10]=2[CH3:37])[C@@H:5]([C:38]2[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(O[C@H]2CC(F)(F)CC[C@@H]2c2ccnn2C)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 79.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (51 mg, 0.081 mmol) prepared in Example 84a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL) and dichloromethane (2.0 mL), to yield the title compound (31 mg, 79%) as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-].CCO>[Fe].O>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3sccc23)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3sccc23)C1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a vial containing tert-butyl [(3S)-1-(5-nitrothieno[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (228.4 mg, 0.6035 mmol), iron powder (357.7 mg, 6.405 mmol) and NH4Cl (567.8 mg, 10.61 mmol), EtOH (5.00 mL) was added, followed by water (1.00 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was then filtered through a pad of diatomaceous earth. The diatomaceous earth pad was eluted with a 10% aq. K3PO4 (30 mL), and EtOAc (30 mL). The organic layer was washed with brine (30 mL), then dried over Na2SO4, and concentrated under reduced pressure. The resulting residue (212.9 mg) was used in the next step without further purification. LCMS calc. for C17H25N4O2S (M+H)+: m/z=349.2. found 349.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][CH:35]([NH2:38])[CH2:36][OH:37].[I-].[Na+]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:38][CH:35]([CH3:34])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: CC(N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNC(C)CO)CC2)nc1N
Temperature: 150 °C
Yield: 65.2 %

Procedure:
The reaction mixture of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.198 mmol, Example 226), dl-2-amino-1-propanol (158 uL, 1.980 mmol, TCl) and sodium iodide (30 mg, 0.198 mmol) in tetrahydrofuran (4 mL) was heated at 150° C. for 1 hour using a Smith Creator microwave synthesizer. Upon cooling to room temperature, the solvent was removed and acetonitrile (3 mL) was added. The mixture was filtered and trifluoroacetic acid (0.25 mL) was added. Purification by reverse phase HPLC (Cl8, eluting with acetonitrile and water) gave (4-amino-2-[1-[3-(2-hydroxy-1-methyl-ethylamino)-propane-1-sulfonyl]-piperidin-4-ylamino]-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone (70 mg, 65% yield) as off-white solids. HR-MS (ES, m/z) calculated for C23H33N6O5SF2[(M+H)+] 543.2196, observed 543.2202.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([NH:14][C:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[N:16][CH3:17])#[N:13]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][NH:18][C:15]([NH:16][CH3:17])=[N:14][C:12]#[N:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN=C(NC#N)NCCCCCO
Solvent: c1ccncc1
Product: CNC(=NC#N)NCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 40 h
Yield: 42.9 %

Procedure:
A solution of p-toluenesulphonyl chloride (9.11 g) in pyridine (40 ml) was added in portions to a stirred solution of N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine (8.0 g) in pyridine (40 ml) at -10°. The mixture was stirred at 2° for 40 hours and was poured into ice-water. The aqueous mixture was extracted with chloroform, and the extracts were washed with dilute hydrochloric acid and evaporated to give 5-(N'-cyano-N"-methylguanidino)pentyl p-toluenesulphonate (6.3 g) as an orange oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[CH:5]=1)[CH:2]=[CH2:3].[C:28]([OH:31])(=[O:30])[CH3:29]>C([O-])(=O)C.[Ag+]>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]2[CH:16]=[C:15]([CH2:17][CH:18]=[CH2:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:31][C:28](=[O:30])[CH3:29])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)O
Reactant: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCCCCBr)c1
Agent: [Ag+]
Agent: CC(=O)[O-]
Product: C=CCc1ccc(O)c(-c2cc(CC=C)ccc2OCCCCCCOC(C)=O)c1

Procedure:
A mixture was prepared by adding 0.2 g of 4-allyl-2-[5-allyl- 2-(6-bromohexyloxy)phenyl]phenol and 0.1 g of silver acetate to 3 ml of acetic acid. The mixture was refluxed by heating for 2 hours and concentrated. The concentrate was extracted with diethylether. The extract was washed with solution sodium hydrogencarbonate and an aqueous solution saturated with NaCl, dried with sodium sulfate and concentrated. The concentrate was purified by a silica gel column-chromatography (n-hexane:ethyl acetate=15:1) to yield 0.12 g of 4-allyl-2-[5allyl-2-(6-acetoxyhexyloxy)phenyl]phenol.