Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:5])[CH3:4].C(N(CC)CC)C>CS(C)=O>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[C:3]([CH3:5])([CH3:4])[CH:2]=[O:1]
Reactant: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
11.9 g of sulfur trioxide pyridine complex dissolved in 75 ml DMSO was added over a period of 20 minutes at room temperature to a solution of 5.48 g of 2-(2-hydroxy-1,1-dimethyl-ethyl)-isoindole-1,3-dione from Step 1 and 7.59 g of triethylamine in 780 ml DMSO. The reaction mixture was stirred at room temperature for 30 minutes, poured onto ice/water and extracted 3 times with tert-butyl methyl ether. The organic was washed with 1N HCl and 2 times H2O, dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 4.92 g crystals (mp 80-82° C.), which were used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1Br
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1NCc1ccccc1

Procedure:
A mixture of 0.31 g. of 4-bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and 0.76 ml. of benzylamine is stirred at 100° C for 2 hours and then added to 25 ml. of aqueous acetic acid and cooled in ice. A precipitate is collected by filtration which weighs 0.26 g. after drying, which gives after recrystallization from a ethylacetate/benzene/petroleum benzene mixture 0.17 g. of 4-benzylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 188°-190° C.
Reaction SMILES: C1O[C:4]([C@@H:6]2[C@:23]3([CH3:24])[C@H:9]([C@H:10]4[C@H:20]([C@H:21]([NH2:25])[CH2:22]3)[C@:18]3([CH3:19])[C@H:13]([CH2:14][C@H:15]([OH:29])[C@@H:16]([O:26][CH2:27][CH3:28])[CH2:17]3)[CH2:12][CH2:11]4)[CH2:8][CH2:7]2)([CH3:5])[O:3]C1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)C.Cl.O>[CH:31]1([NH:25][C@@H:21]2[CH2:22][C@@:23]3([CH3:24])[C@@H:9]([CH2:8][CH2:7][C@@H:6]3[C:4](=[O:3])[CH3:5])[C@H:10]3[C@H:20]2[C@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11]3)[CH2:14][C@H:15]([OH:29])[C@@H:16]([O:26][CH2:27][CH3:28])[CH2:17]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](N)C[C@]2(C)[C@@H](C4(C)OCCO4)CC[C@@H]32)C[C@@H]1O
Reactant: O=C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCO
Solvent: O
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@H](NC2CCCCC2)C[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C[C@@H]1O

Procedure:
A solution of 11α-amino-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one 20-ethylene acetal (2 g) in ethanol (20 ml) was stirred with cyclohexanone (1.5 ml) and sodium cyanoborohydride (2.015 g) for 6 h. 5% NaHCO3 solution (40 ml) was added and the mixture was extracted with ether (x2). The extract was washed with water (x2), dried and evaporated to leave a froth which was dissolved in 2M-HCl solution (50 ml) and ethanol (50 ml). Water (100 ml) was added and the mixture was washed with ether (x2). The wash was extracted with 2M-HCl solution and the combined acid fraction was brought to basic pH with 2M-NaOH solution. The mixture was extracted with ether (x2) and the extract was washed with water (x2), dried and evaporated to leave a froth which was purified by column chromatography eluted with CHCl3 :MeOH (9:1) to give the title compound (1.235 g), [α]D +39°. νmax 1695 cm-1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[Br:16]N1C(=O)CCC1=O>C(Cl)Cl>[Br:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCOCc1ccsc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCOCc1ccsc1Br

Procedure:
3-Butoxymethylthiophene (6.17 grams, 36.24 mmol) was dissolved in 100 milliliters of CH2Cl2, and then 100 milliliters of acetic acid (AcOH) were added. N-Bromosuccinimide (NBS) (6.45 grams, 36.24 mmol) was then added in portions to the resulting mixture under stirring. The mixture resulting was then stirred at room temperature, about 23° C. to about 27° C., for 24 hours. Reaction completion was determined by 1H NMR. The solvents were then removed by evacuation. The residue remaining was dissolved in hexane, and the soluble part was passed through a short silica gel column (10 centimeters×3 centimeters). After removing the solvent, the resulting colorless liquid was purified by column chromatography using hexane/CH2CI2 (3/2, v/v) then by distillation under reduced pressure.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5]1.C([Li])CCC.[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:39](=[O:44])NCOC)[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:19]([O:26][CH2:27][CH2:28][CH2:29][CH:30]([C:39](=[O:44])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5]1)[CH2:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCNC(=O)C(CCCOCc1ccccc1)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)CC1CC(C=C(Br)Br)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)CC1CC(C#CC(=O)C(CCCOCc2ccccc2)CC(=O)OC(C)(C)C)C1
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
1-(2,2-dibromovinyl)-3-(2,2-dimethylpropyl)cyclobutane (5 g) and tetrahydrofuran (50 mL) were mixed. To the mixture was added n-butyllithium (1.65 M in hexane) (20.5 mL) dropwise at −78° C. The mixture was stirred at ice temperature for 30 min. and a solution of tert-butyl 6-benzyloxy-3-(methoxymethylcarbamoyl)hexanoate (4.13 g) in tetrahydrofuran (25 mL) was added dropwise to the mixture. After stirring at ice temperature for 20 min., saturated aqueous ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/20) to give the title compound (3.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(O)[CH:18]=[CH:17]C=[CH:15][CH:14]=1>[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[O-]C1C=CC=CC=1.[Ti+4].C1(O)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5]([O:7][C:8]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1)=[O:6].[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Oc1ccccc1
Agent: [Ti+4]
Agent: COC(=O)c1cc(C)cc(C)c1
Agent: [O-]c1ccccc1
Product: Cc1cc(C)cc(C(=O)Oc2ccccc2)c1

Procedure:
Into this autoclave were charged methyl 3,5-dimethylbenzoate 90 g (550 mmole), phenol 207 g (2200 mmole) and titanium tetraphenoxide/phenol adduct 2.8 g (5.5 mmole) in a state such that the phenol was melting. The autoclave was sealed and then cooled with ice. After sufficient cooling, the inner gas was evacuated with a vacuum pump. Then, the contents were heated and reacted for three hours at 230° C. Furthermore, during the reaction, the liquid held in the reservoir was continuously removed with a pump at a rate of 10 g per hour. After cooling, the reaction mixture in the autoclave was separated by distillation to obtain phenyl 3,5-dimethylbenzoate (product) in an amount of 85 g (68% yield in terms of methyl 3,5-dimethylbenzoate). The boiling point was 155° C./2 mmHg, and the melting point was 32° C.
Reaction SMILES: C([C:3]1([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:8][CH2:7][CH2:6][C:5](=O)[CH2:4]1)C.[CH3:15][NH:16][NH2:17]>C(O)CC>[CH:3]1([C:10]2[CH2:11][C:12](=[O:14])[N:16]([CH3:15])[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCC1(CCC(=O)O)CCCC(=O)C1
Reactant: CNN
Solvent: CCCO
Product: CN1N=C(C2CCCCC2)CC1=O

Procedure:
To ethyl 3-oxo-cyclohexanepropionic acid (4.4 g, 0.234 mole) in n-propanol (500 ml) is added dropwise with stirring under nitrogen at 80°C. methylhydrazine (13.8 g, 0.3 mole). After heating at reflux during 5 hours, the reaction is cooled and evaporated to a residual oil. Crystallization from ethylacetate gives a white powder mp 170.5°C. to 172°C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][O:23][CH3:24])([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(OCC)(=O)C>[ClH:25].[CH3:24][O:23][CH2:22][C:11]1([S:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COCC1(Sc2cccc(C)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC1(Sc2cccc(C)c2)CCNCC1

Procedure:
A solution of N-tert-butoxycarbonyl-4-methoxymethyl-4-(3-tolylsulfanyl)piperidine (0.18 g) in ethyl acetate (25 mL) at 0° C. was saturated with hydrogen chloride gas. The resultant solution was stirred at 0° C. for one h. The product solution was concentrated under vacuum to provide the title compound.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.O[N:60]=[C:61]([NH2:69])[C:62]1[CH:67]=[CH:66][C:65]([CH3:68])=[CH:64][CH:63]=1>O1CCOCC1.CN(C=O)C.C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([N:8]([CH2:7][C:6]([OH:5])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]4[O:39][N:69]=[C:61]([C:62]5[CH:67]=[CH:66][C:65]([CH3:68])=[CH:64][CH:63]=5)[N:60]=4)=[CH:41][CH:42]=3)=[O:32])=[CH:15][CH:14]=2)=[O:31])=[C:20]([C:27]([F:29])([F:28])[F:30])[CH:21]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Reactant: Cc1ccc(C(N)=NO)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4nc(-c5ccc(C)cc5)no4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (141 mg, 0.235 mmol) and 4-methylmorpholine (57.0 μl, 0.52 mmol) in dioxane (4 mL) was added isobutyl chloroformate (31.0 μl, 0.24 mmol). After 1 h, the reaction mixture was added through a frit to a stirred solution of N′-hydroxy-4-methylbenzimidamide (38.8 mg, 0.258 mmol) in DMF (2 mL). After stirring at room temperature for 1 h, the reaction mixture was heated to 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature, diluted with DCM (4 mL), washed with NaHCO3 (10 mL), split through a hydrophobic frit and evaporated. The crude material was purified by column chromatography (EA/isohexanes). The isolated material was taken up in DCM (2 mL), treated with TFA (2 mL) and allowed to stir for 2 h. The solvents were evaporated and the residue purified by preparative HPLC to afford 22 mg (14%) of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(3-(p-tolyl)-1,2,4-oxadiazol-5-yl)benzyl)benzamido)acetic acid 363 as a white solid. LCMS-ESI (m/z) calculated for C35H29F3N4O6: 658; found 659 [M+H]+, tR=8.01 min (Method 9). 1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 10.34 (s, 1H), 8.32-8.11 (m, 2H), 8.11-7.86 (m, 2H), 7.71-7.52 (m, 4H), 7.50-7.29 (m, 5H), 7.26-7.16 (m, 2H), 4.78 (s, 1H), 4.71 (s, 1H), 4.05 (s, 1H), 3.99 (s, 1H), 3.92-3.76 (m, 5H), 2.42 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([S:9][C@H:10]1[CH2:14][C@@H:13]([C:15]([NH:17][CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=O)[N:12]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:11]1)(=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([S:9][C@H:10]1[CH2:14][CH:13]([C:15]2[N:23]3[C:19]([S:20][CH:21]=[CH:22]3)=[CH:18][N:17]=2)[N:12]([C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25])[CH2:11]1)(=[O:8])[CH3:7]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)NCc1nccs1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)CC1c1ncc2sccn12
Temperature: 100 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
Phosphorus oxychloride (1.2 ml) is added to a solution of 1.00 g of (3S,5S)-3-acetylthio-1-allyloxycarbonyl-5-[(thiazol-2-yl)methylaminocarbonyl]pyrrolidine in 10 ml of toluene, and the mixture is stirred at 100° C. for one hr. The reaction mixture is concentrated under reduced pressure, dichloromethane is added to the residue, and the mixture is successively washed with an aqueous potassium carbonate solution and saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation, and the residue is purified by column chromatography on silica gel to give 0.27 g of the title compound (stereoisomer A: a high polar component) and 0.07 g of the title compound (stereoisomer B: a low polar component).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH2:23]([O:30][NH2:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][N:31]=[C:18]([CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:21])[CH3:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NOCc1ccccc1
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Agent: Cl
Product: CC(CCCn1c(C)nc2c(N)nc3ccccc3c21)=NOCc1ccccc1

Procedure:
By the general method described in Part F of Example 30, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one was reacted with O-benzylhydroxylamine hydrochloride to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one O-benzyloxime) in about a 3 to 1 mixture of E and Z isomers as white crystals after recrystallization from a mixture of toluene and hexane, mp 146-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:6]2=[CH:5][C:4]=1[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1>CO.[Pt](=O)=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:12]([CH:13]([CH3:15])[CH3:14])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:20])[CH3:21])[C:6]2=[CH:5][C:4]=1[CH:22]1[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:26][CH2:27]1
Reactant: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Pt]=O
Solvent: CO
Product: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To colorless solution of tert-butyl 4-(5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (998 mg, 2.055 mmol) in MeOH (30 mL) was added platinum(IV) oxide (98 mg, 0.432 mmol) at rt. The mixture was shaked on Par Shaker for 3 hr under H2 (55 psi). The mixture was filtered with MeOH (20 mL), concentrated on rotary vacuo to afford the expected product, tert-butyl 4-(5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)piperidine-1-carboxylate (995 mg, 100%) as a light grey solid. Mass spec 488.27 Calc for C27H45N3O3Si 487.32, which was pure enough to be used in next reaction.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([O:14][C:15]1[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=1)=[C:9]([C:30]1[S:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[CH:8]=[CH:7]2.B(Br)(Br)Br.Cl>ClCCl.CO>[CH3:35][C:32]1[S:31][C:30]([C:9]2[C:10]([O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[C:11]3[C:6](=[CH:7][CH:8]=2)[CH:5]=[C:4]([OH:3])[CH:13]=[CH:12]3)=[CH:34][CH:33]=1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C)s3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)s1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 97.8 %

Procedure:
Dissolve 1-(2-(4-(6-methoxy-2-(5-methylthiophen-2-yl)naphthalen-1-yloxy)phenoxy)ethyl)piperidine hydrochloride (5.15 g, 10.1 mmol) in dichloromethane (340 mL). Cool the resulting solution to 0° C. In a separate container under nitrogen combine neat boron tribromide (3.9 mL, 40.4 mmol) and dichloromethane (36.5 mL). Add the resulting boron tribromide solution to the cooled solution. Stir the resulting mixture at 0° C. for 2.5 hours. Quench the mixture with saturated aqueous sodium bicarbonate and allow it to warm to room temperature. Separate the layers and extract the aqueous layer with 20% methanol in dichloromethane (10 mL×3). Concentrate the combined organic solutions to give a solid. Slurry the solid in methanol (234 mL) and add HCl (1N in water; 10.8 mL). Load the resulting solution onto an SCX acidic ion exchange column. Flush the column with 40% methanol in dichloromethane then elute desired material with 40% 7M ammonia in methanol in dichloromethane. Concentrate the ammonia containing eluent to give the title compound (4.54 g, 9.88 mmol). LRMS (m/z): 460 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.CS[C:20]1[N:21]=[C:22]([OH:29])[C:23]2[S:28][CH2:27][CH2:26][C:24]=2[N:25]=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:20]3[N:21]=[C:22]([OH:29])[C:23]4[S:28][CH2:27][CH2:26][C:24]=4[N:25]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CSc1nc(O)c2c(n1)CCS2
Reactant: Clc1ccc(N2CCNCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Temperature: 180 °C
Yield: 92.8 %

Procedure:
20.45 g 1-(4-chloro-phenyl)-piperazine are placed in 5.95 ml (104 mmol) glacial acetic acid and heated to 180° C. 8.01 g 2-methylsulphanyl-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ol are added, the non-stirrable reaction mixture is heated for 2.5 hours to 180° C. After cooling, water is added, the precipitate is suction filtered and dried in the air. The substance is treated with ethanol under ultrasound, suction filtered and dried. 12.95 g of the product are obtained as a powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:29][C:30]1[CH:31]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:33]=[C:32]([NH:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2cc(F)cc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(F)cc(NS(C)(=O)=O)c3)n(-c3ccccc3)c(=O)c12
Yield: 57.3 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (30 mg, 0.07 mmol) was treated with N-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (34 mg, 0.11 mmol, prepared as described at WO 2004052847 A2 20040624), cesium carbonate (2M, 110 μl, 0.22 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (6 mg, 0.01 mmol) according to the method described in Example 3 to give 22 mg (59% yield) of the title compound. Purity 100%.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][C:21]1[CH:22]=[C:23]([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1.[Br-].[K+]>C(#N)C1C=CC=CC=1.[Ni](Br)Br>[Br-:20].[C:14]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[C:12]([P+:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:23]3[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=3)[CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(P(c2ccccc2)c2ccccc2)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Br[Ni]Br
Agent: [Br-]
Agent: [K+]
Solvent: N#Cc1ccccc1
Product: c1ccc(P(c2ccccc2)c2cccc([P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of nickel (II) bromide (dry under vacum for 2 h at 140° C.) (3.6 g, 16 mmol, 0.5 equiv) in benzonitrile (dry overnight on activated 4A molecular sieves) (250 mL) was added triphenylphosphine (26.0 g, 49 mmol, 3 equiv). The solution was heated under reflux for 15 min and then cooled to room temperature. (3-bromophenyl)diphenylphosphine (2) (11.1 g, 32.5 mmol, 1.0 equiv) in benzonitrile (20 mL plus rinse 5 mL) was added to the solution. The resulting solution was heated under reflux for 4 h then cooled to room temperature. A 10% (w/w) aqueous solution of potassium bromide (250 mL) was added. The layers were separated, and the aqueous layer was washed two times with CH2Cl2 (250 mL). The organic layer was washed three times with water (100 mL) and dried over anhydrous MgSO4, filtered, and concentred under reduced pressure. To the resulting solution was added hexane (750 mL) to precipitate the crude product. The precipitate was filtered and washed with hexane and then dissolved in CH2Cl2 (20 mL). Et2O (150 mL) was then added and the mixture was filtered. The resulting solid was purified by flash chromatography (MeOH/CH2Cl2, 0:100-10:90) to afford (3-diphenylphosphinophenyl)triphenylphosphonium bromide (3) (>95% purity) as a white solid (15.3 g, 78%), which was characterized as follows:
Reaction SMILES: C(#N)C.C(O[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C([Cl:21])=O.Cl>C(N(CC)CC)C>[ClH:21].[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)N1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An acetonitrile (7 ml) solution containing N-(tert-butoxycarbonyl)piperazine (700 mg), N-methyl-N-phenylcarbamoyl chloride (700 mg) and triethylamine (1.05 mL) was stirred at room temperature for 15 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 1-(N-methyl-N-phenylaminocarbonyl)piperazine hydrochloride.