Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[C:18]([O:19]C(=O)C(C)C)=[C:17]([F:25])[C:16]([F:26])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1>O1CCCC1.Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:11](=[O:12])[CH:13]([CH3:18])[CH3:14])[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:26])=[C:17]([F:25])[C:18]=2[OH:19])=[O:12])=[CH:8][CH:9]=1
Reactant: CC(C)C(=O)Oc1c(C(=O)Cc2ccc(Cl)cc2)ccc(F)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=O)C(C(=O)c1ccc(F)c(F)c1O)c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
Sodium hydride (1.5 g, 37.5 mmol, 60% dispersion in mineral oil, 4 eq.) is added portionwise to a stirred solution of isobutyric acid 6-[2-(4-chlorophenyl)acetyl]-2,3-difluorophenyl ester (3.16 g, 8.97 mmol) in tetrahydrofuran (60 ml) over 15 min. The mixture is heated in an oil bath at 80° C. for 4 h. The reaction is cooled to room temperature, diluted with 2M HCl solution and washed with ethyl acetate. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound as a brown oil. The product is used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.O=[CH:12][C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[N:9]=[C:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)[CH:12]=[N:10]2
Reactant: COC(=O)c1ccc(C(=O)C=O)cc1
Reactant: COc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3n2)cc1

Procedure:
To a solution of methyl 4-acetylbenzoate (1.00 g, 5.61 mmol) in DMSO (5 mL) was slowly added 40% HBr (1.5 mL) at 20° C. under stirring. The mixture was stirred at 60° C. for 12 hours. The mixture was diluted with water (10 mL) and the resulting mixture was extracted with DCM (10 mL×3), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give methyl 4-(2-oxoacetyl)benzoate (150 mg), which was taken forward without further purification. To a solution of 4-methoxybenzene-1,2-diamine (107 mg, 0.78 mmol) in 5 mL of acetic acid was added the crude methyl 4-(2-oxoacetyl)benzoate (150 mg). The mixture was refluxed for 2.5 hours. The solvent was removed in vacuo. The crude product was purified by prep-TLC (PE/EA: 1/1) to separate the desired methyl 4-(6-methoxyquinoxalin-2-yl)benzoate (more polar) from the undesired methyl 4-(7-methoxyquinoxalin-2-yl)benzoate. The two structures were confirmed by HMBC spectra.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>OS(O)(=O)=O>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(N)n1
Agent: O=S(=O)(O)O
Product: Cc1cccc(N[N+](=O)[O-])n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-amino-6-methylpyridine (38 g, 352 mmol) in conc. H2SO4 (70 mL) at 0 ° C. was added HNO3 (16.5 mL, d=1.49) drop-wise over 30 min. The mixture was warmed stirred an additional 1 h at 0° C. then poured into 500 g of ice. This heterogeneous mixture was stirred for 1 h at r.t., filtered, washed with 50 mL H2O and the residue was briefly dried to give 58 g of crude moist 6-methyl-2-nitraminopyridine. This solid was carefully added in 1-2 g portions to stirred H2SO4 (70 mL) at 40° C. After complete addition, the reaction mixture was stirred 1 h at 40° C., cooled and poured into 500 g of ice. The resulting precipitate was filtered, washed with 50 mL of H2O, and air dried to give a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].I[CH2:20][CH3:21]>CN(C)C=O>[CH2:20]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1)[CH3:21]
Reactant: CCI
Reactant: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(OC)(OC)C(OCC)C1
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
To a stirred solution of 35 parts of ethyl 3-hydroxy-4,4-dimethoxy-1-piperidinecarboxylate in 144 parts of N,N-dimethylformamide were added portionwise 8.2 parts of a sodium hydride dispersion 50% at about 30° C. After stirring for 1.50 hours at about 30° C., the mixture was cooled to room temperature and 26.5 parts of iodoethane were added dropwise at a temperature below 30° C. Upon completion, stirring was continued for 18 hours at room temperature. The reaction mixture was poured onto water and the product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated, yielding 34.1 parts (87%) of ethyl 3-ethoxy-4,4-dimethoxy-1-piperidinecarboxylate as a residue (intermediate 67).
Reaction SMILES: [CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([NH:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)N1CCNCC1
Yield: 130.4 %

Procedure:
To a solution of benzyl 4-(isopropylcarbamoyl)piperazine-1-carboxylate (3, 3.94 g, 12.9 mmol) in methanol (100 mL) was added 10% Pd/C (50% wet, 0.400 g) and the mixture was stirred under 1 atmosphere of hydrogen for 16 h. After this time, the mixture was filtered through Celite and the filtrate concentrated to afford the title compound (2.88 g, >99%): 1H NMR (300 MHz, CD3OD) δ 4.00-3.80 (m, 1H), 3.45-3.35 (m, 4H), 2.88-2.78 (m, 4H), 1.13 (d, J=6.5 Hz, 6H); Multimode MS m/z 172 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O.[NH2:21][NH2:22]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][C:16](=[O:18])[NH:21][N:22]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NN
Reactant: Cc1nccn1-c1ccc(C(=O)CCC(=O)O)cc1
Solvent: O
Product: Cc1nccn1-c1ccc(C2=NNC(=O)CC2)cc1

Procedure:
Similarly, reaction of 4-(2-methyl-1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with hydrazine hydrate according to the procedure of this Example gives 4,5-dihydro-6-[4-(2-methyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone.
Reaction SMILES: [CH2:1]([C:3]([CH3:19])([CH2:17][CH3:18])[C:4](=[O:16])CC(N)(P(O)(=O)O)P(O)(=O)O)[CH3:2].N([O-])=[O:21].[Na+]>O>[CH2:17]([C:3]([CH3:19])([CH2:1][CH3:2])[C:4]([OH:16])=[O:21])[CH3:18]
Reactant: O=N[O-]
Reactant: CCC(C)(CC)C(=O)CC(N)(P(=O)(O)O)P(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCC(C)(CC)C(=O)O
Temperature: 50 °C
Reaction time: 7 h

Procedure:
0.20 mol (63.4 g) 4-ethyl-4-methyl-3-oxo-1-aminohexane-1,1-di-phosphonic acid (IV) R2 =R3 =CH2CH3, R4 =CH3) were suspended in 600 ml 2N hydrochloric acidd and a solution of 0.8 mol (55.2 g) sodium nitrite dissolved in 1104 ml water were added dropwise to the resulting suspension with stirring over a period of 7 hours at 50° C. 2-Ethyl-2-methyl-butyric acid was formed as the organic phase and was extracted with ether. Unused nitrous acid was removed with hydrazine before working up. The aqueous phase was concentrated to around 300 ml in a rotary evaporator and alkylized to pH 9 with sodium hydroxide. The tetrasodium salt of hydroxyacetonitrile diphosphonic acid (III, M=Na) crystallized out from the cold solution in the form of the octahydrate. The yield comprised 65% (58.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:12])[F:13])[N:4]=1
Reactant: COc1nc(C(F)(F)F)ccc1C#N
Agent: [Pd]
Solvent: CO
Product: COc1nc(C(F)(F)F)ccc1CN
Yield: 79 %

Procedure:
The nitrile 28c (0.48 g, 2.33 mmol) was solubilized in MeOH (30 mL) and to the solution was added Pd/C 10% (0.3 g). The mixture was hydrogenated at 70 psi overnight. The reaction mixture was filtered through a celite pad, the filtrate was evaporated at reduce pressure to furnish 29c as yellow oil (0.38 g, 1.84 mmol, 79% Yield) used without further purification.
Reaction SMILES: [C:1]([C:3]([C:9]#[N:10])=[C:4]([C:7]#[N:8])[C:5]#[N:6])#N.[CH2:11]([N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[S:25]C=[CH:27][CH:28]=2)=[C:18]([O:29][CH3:30])[CH:17]=1)[CH2:12][CH2:13][CH3:14]>CN(C)C=O>[C:5]([C:4](=[C:3]([C:1]1[S:25][C:24]([CH:23]=[CH:22][C:19]2[CH:20]=[CH:21][C:16]([N:15]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][C:18]=2[O:29][CH3:30])=[CH:28][CH:27]=1)[C:9]#[N:10])[C:7]#[N:8])#[N:6]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OC)c1
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C(C#N)=C(C#N)C#N)s2)c(OC)c1
Temperature: 50 °C
Yield: 41.8 %

Procedure:
In 7 ml of N,N-dimethylformamide, 235 mg (1.83 mmol) of tetracyanoethylene was dissolved. With stirring under ice cooling, 600 mg (1.75 mmol) of dibutyl[3-methoxy-4-[2-(thiophene-2-yl)vinyl]phenyl]amine was dissolved in 2 ml of N,N-dimethylformamide and added dropwise. The mixture was stirred for 1.5 hours. After the ice bath was removed, the mixture was stirred at room temperature for 1 hour and further stirred with heating at 50° C. overnight. After the reaction mixture was poured into 80 ml of water, extraction with chloroform, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography and washed with methanol to give 324 mg of a dark reddish crystal having a mp of 189-192° C. (yield: 41.8%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[NH:6][CH2:7]2.ClN1C(=O)CCC1=O.[OH-].[K+].O>C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[N:6]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2CN1
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Dissolve (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,2,3,4-tetrahydroisoquinoline (4.2 g, 11.8 mmol) in diethyl ether (118 mL). Add N-chlorosuccinimide (2.36 g, 17.7 mmol). Stir 30 min at room temperature and concentrate under reduced pressure. Dissolve the residue in potassium hydroxide (42.0 mL, 30.3 mmol, 5% in MeOH) and stir for 30 min at room temperature. Pour into water and extract with dichloromethane. Dry the dichloromethane extracts over sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography eluting with ethyl acetate: hexanes (5-100% gradient) to give the title compound (3.40 g, 9.59 mmol). MS (m/z): 354 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[F:11][C:2]([F:1])([F:10])[C:3]1[N:8]=[C:7]([NH:9][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(C(F)(F)F)n1)C(=O)OCC
Temperature: 95 °C

Procedure:
A mixture of 6-trifluoromethylpyridin-2-amine (17.2 g) and diethyl ethoxymethylenemalonate (22.9 g) was heated at 95° C., under vacuum for 8 hours. The mixture was cooled and diluted with petroleum ether b.p. 60°-80° C. (50 ml). The mixture was filtered and the residue was recrystallised from IMS to give diethyl 2-(6-trifluoromethyl-2-pyridylaminomethylene)malonate, m.p. 125°-128° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][CH:13]([CH2:35][OH:36])[CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)=[O:16])=[CH:4][C:3]=1[Cl:37]>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5]([CH2:12][CH:13]([CH2:14][C:15](=[O:16])[N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:29][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[NH:25][C:24]3=[O:34])[CH2:21][CH2:22]2)[CH:35]=[O:36])=[CH:4][C:3]=1[Cl:37]
Reactant: Nc1c(Cl)cc(CC(CO)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Solvent: ClCCl
Product: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 0.539 g (1.000 mmol) 3-{1-[4-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-3-hydroxymethyl-butyryl]-piperidin-4-yl}-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one (Intermediate product 35) in 10 mL dichloromethane was added 0.933 g (2.200 mmol) Dess-Martin-Periodinane and the mixture was stirred for 3 hours at RT. The reaction mixture was washed with sat. aqueous sodium thiosulphate solution and sat. aqueous NaCl solution, dried over sodium sulphate and evaporated down i. vac. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 50:1→25:1 v/v).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>O>[CH2:18]([O:23][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a dimethylformamide solution (364 ml) containing 2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) was added sodium hydride (60% contained, 27.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 2-neopentyloxy-5-nitrobenzonitrile (105 g). Subsequently, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml) and the mixture was heated to 65° C. 2-Neopentyloxy-5-nitrobenzonitrile (80.5 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g). melting point: 55-56° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[S:24][CH2:23][C:22](=O)[CH2:21][C:20]2=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:22]2[CH2:21][C:20]3[C:19]4[C:28](=[CH:29][CH:30]=[C:17]([O:16][CH3:15])[CH:18]=4)[N:27]=[CH:26][C:25]=3[S:24][CH2:23]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ncc3c(c2c1)CC(=O)CS3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)OC(C)(C)C)CC1)CS3
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A solution of piperidin-4-yl-carbamic acid tert-butyl ester (2.45 g, 12.22 mmol, 2.0 eq), 6-methoxy-4H-1-thia-9-aza-phenanthren-3-one (1.50 g, 6.11 mmol, 1.0 eq) and p-toluenesulfonic acid (526 mg, 3.06 mmol, 0.5 eq) in toluene (50 mL) is heated at 120° C. for 2 hours. The resulting solution is cooled down to room temperature, solvent is removed and the crude is dissolved in dichloromethane (100 mL) and methanol (100 mL) before the addition of acetic acid (0.5 mL, 8.66 mmol, 1.4 eq) and sodium cyanoborohydride (1.24 g, 19.73 mmol, 3.2 eq). After 1 h30 stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×50 mL) and a saturated sodium hydrogen carbonate aqueous solution (50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate:ammonia-7N solution in methanol, 1:1:0.05, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester as a light yellow solid (746 mg, 28% yield).
Reaction SMILES: [CH:1]([C@@H:14]1[O:19][CH2:18][C@@H:17](OS(C)(=O)=O)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@H:17]1[CH2:16][CH2:15][C@@H:14]([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:19][CH2:18]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 91.3 %

Procedure:
Trans-2-diphenylmethyl-tetrahydropyran-5-yl methanesulfonate 13 (0.39 g, 1.12 mmol) in dry DMF (50 ml) was reacted with sodium azide (0.22 g, 3.35 mmol) to yield cis-5-azido-2-diphenylmethyl-tetrahydropyran 14 (0.3 g, 92%) as an oil (Procedure B).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]O)=[CH:8][O:9][C:5]=2[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:34]I.N1C=CN=C1>C1COCC1>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][I:34])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CCO)coc2c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(CCI)coc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(6-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was then extracted with chloroform, washed well with 5% NaS2O3 solution and the organic layer was dried over anhydrous MgSO4. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, namely 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.2 g (80%); 302 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.[CH3:48][O:49][C:50]1[CH:51]=[C:52]([C@H:56]([NH2:58])[CH3:57])[CH:53]=[CH:54][CH:55]=1>O>[Br:1][C:2]1[S:3][C:4]([C:7]([NH:58][C@@H:56]([C:52]2[CH:53]=[CH:54][CH:55]=[C:50]([O:49][CH3:48])[CH:51]=2)[CH3:57])=[O:9])=[CH:5][N:6]=1
Reactant: O=C(O)c1cnc(Br)s1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@@H](C)NC(=O)c2cnc(Br)s2)c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2-bromothiazole-5-carboxylic acid (0.3 g, 1.442 mmol), diisopropyl ethylamine (0.205 g, 1.586 mmol) and HATU (0.603 g, 1.586 mmol) in dimethylformamide (7.21 mL, 1.442 mmol) was added (R)-1-(3-methoxyphenyl)ethanamine (0.218 g, 1.442 mmol) dropwise. After stirring for 12 hours at 50° C., the reaction was poured into water (50 mL). The precipitated solid was then collected by filtration washing successively with water (2×50 mL) and hexanes (2×50 mL). The recovered product was used without further purification in the next step.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.N1C=CC=CC=1.CCOCC>C1COCC1>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C(=O)O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCC(C(=O)O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
Benzoylchloride (7.84 g, 0.057 mol) was added dropwise to a solution of 2-(4'-aminophenyl)butyric acid (10.0 g, 0.057 mol) and pyridine (4.85 g, 0.061 mol) in 100 mL of THF at 0° C. After 30 minutes the ice bath was removed and the reaction warmed to room temperature. After 1 hour the suspension was diluted with 300 mL of ether, washed with 10% HCl (3×50 mL), saturated NaCl (50 mL), dried over MgSO4 and evaporated to give a brown solid. Trituration with ether afforded 7.54 g (47.7%) of the product as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[C:35]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[CH:34][N:33]=[C:32]([NH2:45])[N:31]=1>>[CH3:29][C:30]1[C:35]([B:36]2[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:44])([CH3:43])[O:37]2)=[CH:34][N:33]=[C:32]([NH2:45])[N:31]=1.[NH2:45][C:32]1[N:31]=[C:30]([CH3:29])[C:35]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: CC(O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(=O)[C@H](C)O)CC3)cc2n1

Procedure:
4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine was prepared according to WO2007/084786. 110 mg of 1-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-2-hydroxypropan-1-one was coupled to 4-methyl-5-(4,4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 50 mg of 324. MS (Q1) 499.2 (M)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16](=[O:19])[NH:17][CH3:18])[C:13]([NH:20][C:21]3[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]4[CH:46]=[CH:45][C:35]([CH2:36][CH2:37][CH2:38][CH2:39][PH:40](=[O:44])[O:41]CC)=[CH:34][C:33]=4[O:47][CH3:48])[N:22]=3)=[CH:12][CH:11]=2)[CH:7]=[N:6]1.Br[Si](C)(C)C>N1C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16](=[O:19])[NH:17][CH3:18])[C:13]([NH:20][C:21]3[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][N:24]=[C:23]([NH:31][C:32]4[CH:46]=[CH:45][C:35]([CH2:36][CH2:37][CH2:38][CH2:39][PH:40](=[O:41])[OH:44])=[CH:34][C:33]=4[O:47][CH3:48])[N:22]=3)=[CH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1
Agent: C[Si](C)(C)Br
Solvent: c1ccncc1
Product: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of ethyl (4-{[4-({6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinate (Compound 37B, 10 mg, 0.015 mmol) in pyridine (1 mL) was charged with bromotrimethylsilane (0.012 mL, 0.087 mmol). The reaction was stirred at rt for 20 min. The material was not isolated. MS (ESI): m/z 663.23 [M+H]+. UPLC: tR=0.85 min (polar—2 min).