Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1CCC[C:8]2NC(=S)C(C#N)=C[C:3]1=2.[NH2:15][C:16]1[CH2:21][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:19][C:18](=[O:28])[CH:17]=1.C(OCC)(=O)C#C>>[C:22]1([CH:20]2[CH2:21][C:16]3[NH:15][C:2](=[O:1])[CH:3]=[CH:8][C:17]=3[C:18](=[O:28])[CH2:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC1=CC(=O)CC(c2ccccc2)C1
Reactant: N#Cc1cc2c([nH]c1=S)CCCC2=O
Agent: C#CC(=O)OCC
Product: O=C1CC(c2ccccc2)Cc2[nH]c(=O)ccc21

Procedure:
In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092), 3-amino-5-phenylcyclohex-2-en-1-one reacted with ethyl propiolate to give the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:13]#[N:14])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:5])[CH3:2].C(N(CC)CC)C>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([CH2:13][NH2:14])[CH2:8][CH:7]1[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C#N)CC1CC(C)C
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CN)CC1CC(C)C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
To a solution of 1-cyano-2-isobutyl-cyclopropanecarboxylic acid ethyl ester (0.41 g, 2.10 mmol) in 45 mL EtOH was added triethylamine (5.0 mL) and Raney nickel (1.0 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 18 hours, filtered, and concentrated. Flash chromatography of the residue (5→10% MeOH/CH2Cl2) provided 0.11 g (26%) of 1-aminomethyl-2-isobutyl-cyclopropanecarboxylic acid ethyl ester as a colorless oil. 1H NMR δ 4.10 (q, J=7.1 Hz, 2H), 2.90 (d, J=14.2 Hz, 1H), 2.76 (d, J=14.2 Hz, 1H), 1.63 (m, 1H), 1.52 (m, 2H), 1.34 (m, 1H), 1.22 (t, J=7.1 Hz, 3H), 1.04 (m, 1H), 0.90 (m, 6H), 0.49 (m, 1H). 13C NMR δ 175.51, 60.75, 42.42, 37.92, 30.61, 29.04, 26.46, 22.91, 22.63, 21.31, 14.49.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Br)c2)cc1
Yield: 56.8 %

Procedure:
Following a procedure similar to that described in Example 3, but using 3.0 g of 2-amino-1-(3-bromophenyl)ethanol (prepared as described in Preparation 41), 3.67 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 3.1 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.33 g of the title compound were obtained having an Rf=0.25 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl>C(O)C1C=CC=CC=1.O.CCO.CCO.CCO.CCO.[Ti]>[O:1]=[C:2]1[N:7]2[CH2:8][C:9]3[C:14]([C:6]2=[C:5]([C:15]([O:17][CH2:18][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Agent: [Ti]
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: OCc1ccccc1
Product: O=C(OCc1ccccc1)c1cc(-c2ccccc2)c(=O)n2c1-c1ccccc1C2
Reaction time: 3 h
Yield: 143.5 %

Procedure:
A solution of 1.62 g of tetraethyl orthotitanate in 71 ml of benzyl alcohol was treated with 4.52 g of methyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate and stirred at 115°-120° under argon for 3 hours. The reaction mixture was then cooled, stirred with 71 ml of 1N hydrochloric acid for 1 hour, diluted with 350 ml of water and extracted several times with methylene chloride. The organic phases were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate, filtered and evaporated. The residue was stirred in 710 ml of diethyl ether for 1 hour, suction filtered and the material obtained was dried in a vacuum. There was obtained 4.02 g of benzyl 4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate as yellowish crystals with a m.p. of 229°.
Reaction SMILES: [Na].S(O)(O)(=O)=O.[C:7]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(=[NH:9])[NH2:8].C(O[CH:26]=[C:27]([C:33]([C:35]([OH:37])=[O:36])=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.[CH2:38](O)[CH3:39]>>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:9]=2)[CH2:11][CH2:12]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(=O)O
Reactant: CCO
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na]
Product: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To absolute ethanol with 0.91 g of sodium dissolved therein, 11.5 g of 1-amidino-4-benzylpiperazine sulfate was added. The resultant mixture was stirred at room temperature for 30 minutes, to which 8.8 g of ethyl ethoxymethyleneoxaloacetate [synthesized by the process described in J. Am. Chem. Soc., 73, 3684 (1951)] was added. After allowing them to react at room temperature for 2 days, the reaction was caused to proceed further for 1 hour while heating the reaction mixture under reflux. After cooling the reaction mixture to room temperature, ethanol was distilled off under reduced pressure and the residue was dissolved in a mixture of water and ethyl acetate. After separation of the water layer, the ethyl acetate layer was washed with water and then with saturated saline. After drying the ethyl acetate layer with magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain 13.7 g of the above-identified compound as light brown crystals (yield: 96%).
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([P:11]([C:18]2C=CC=CC=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)(OC)=O.[C:24]([C:28]1[CH:29]=[C:30]([S:38]([O:41]C)(=[O:40])=[O:39])[CH:31]=[C:32]([C:34]([O:36][CH3:37])=[O:35])[CH:33]=1)([O:26][CH3:27])=[O:25]>>[C:34]([C:32]1[CH:31]=[C:30]([S:38]([O-:41])(=[O:40])=[O:39])[CH:29]=[C:28]([C:24]([O:26][CH3:27])=[O:25])[CH:33]=1)([O:36][CH3:37])=[O:35].[C:34]([C:32]1[CH:33]=[CH:28][C:29]([CH2:18][PH+:11]([C:8]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:30][CH:31]=1)([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)OC)c1
Reactant: COC(=O)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)[O-])c1
Product: COC(=O)c1ccc(C[PH+](c2ccccc2)c2ccccc2)cc1
Temperature: 130 °C

Procedure:
A mixture of 16.0 g (0.05 mol) of p-carbomethoxyphenyldiphenylphosphine and 14.41 g (0.05 mol) of methyl 3,5-bis(carbomethoxy)benzenesulfonate was heated in a 130° C. bath with nitrogen bubbling through the melt for 2.5 hours.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=1.[S:21]([NH2:25])(N)(=[O:23])=[O:22].[F:26][C:27]1[CH:33]=[CH:32][C:30](N)=[CH:29][CH:28]=1>N1C=CC=CC=1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([N:3]2[C@H:2]([CH3:1])[CH2:7][N:6]([S:21]([NH:25][C:30]3[CH:32]=[CH:33][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C@@H:5]([CH3:8])[CH2:4]2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: NS(N)(=O)=O
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1
Reactant: Nc1ccc(F)cc1
Solvent: c1ccncc1
Product: C[C@@H]1CN(S(=O)(=O)Nc2ccc(F)cc2)[C@@H](C)CN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
A 1.21 g portion of trans-4-(2,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile synthesized in Reference Example 1-1 and 2.05 g of sulfamide were heated under reflux for 1.5 hours in 15 ml of pyridine. Next, this was mixed with 4.05 ml of 4-fluoroaniline and again heated under reflux for 4 hours. After evaporation of the solvent, the residue was purified by a silica gel column chromatography to obtain 701 mg of the title compound from toluene-ethyl acetate eluate.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][N:7]=1)=[O:5])C.[CH3:14][O:15][CH2:16][CH2:17][OH:18].[H-].[Na+].[NH3:21]>CN(C=O)C.CCO.[Cu]I>[CH3:14][O:15][CH2:16][CH2:17][O:18][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([C:4]([NH2:21])=[O:5])=[N:7][CH:8]=1
Reactant: N
Reactant: CCOC(=O)c1ncc(Br)cc1C
Reactant: COCCO
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COCCOc1cnc(C(N)=O)c(C)c1
Temperature: 110 °C

Procedure:
5-Bromo-3-methyl-pyridine-2-carboxylic acid ethyl ester (3.3 g, 13.52 mmol) and CuI (0.515 g, 2.70 mmol) were dissolved in 2-methoxy-ethanol (10.29 g, 135 mmol) and DMF (2.5 ml). NaH (60%, 0.541 g, 13.52 mmol) was carefully added and the reaction mixture was warmed to 110° C. for 8 h. The reaction mixture was allowed to cool to rt and NH3 in EtOH (10%, 30 ml) was added. The reaction mixture was placed in an autoclave and heated to 100° C. for 20 h. The reaction mixture was cooled to rt, concentrated and purified by column chromatography (silica gel; DCM/0-4% i-Propanol) to give the desired product (1 g, 4.52 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)CCO)c1
Yield: 100 %

Procedure:
2-(3-Nitrophenylsulfonyl)ethanol (10 g; 43 mmol) was dissolved in 200 ml tetrahydrofuran and 200 mL ethanol, 3 g Pd/C (10%) was added and the mixture treated with hydrogen gas. The solvents were removed to obtain 8.8 g (43 mmol, 100% yield) of the desired compound as colourless oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([CH3:23])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O>C(Cl)Cl.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:7]2[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[O:9][N:8]=2)=[O:12])=[CH:15][C:16]=1[CH3:23]
Reactant: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
To a stirred solution of crude 1-(5-tert-butylisoxazol-3-yl)-3-(3-methyl-4-nitrophenyl)urea (2.0 g, 6.1 mmol) from Step 1 of this example in DCM (10 mL) was added AcOH (1.8 mL, 31.2 mmol), followed by zinc (1.99 g, 31.2 mmol) in small portions. The resulting mixture was stirred at rt for 1 h. LC-MS indicated that the reaction was complete. The reaction mixture was carefully quenched with sat. NaHCO3 (50 mL) at rt, and the resulting biphasic mixture was extracted with EtOAc (50 mL). The organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 0-65% EtOAc in hexanes, to give 1-(4-amino-3-methylphenyl)-3-(5-tert-butylisoxazol-3-yl)urea (560 mg, 61% over two steps). LC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C[N+]1([O-])CC[O:27]CC1.[OH2:31]>O1CCCC1.O=[Os](=O)(=O)=O>[OH:31][C@H:5]1[C@@H:6]([OH:27])[C@@H:1]2[CH2:7][C@H:4]1[CH2:3][CH:2]2[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]
Reactant: NS(=O)(=O)c1ccc(OCC2C[C@H]3C=C[C@@H]2C3)c([N+](=O)[O-])c1
Reactant: O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2C[C@@H]3C[C@H]2[C@H](O)[C@@H]3O)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 201A (340 mg) in tetrahydrofuran (10 mL) and water (1 mL) was added N-methylmorpholine N-oxide (184 mg) and OsO4 (2.5% in 2-methyl-2-propanol) (1.05 mL). The reaction mixture was stirred overnight and purified by reverse phase HPLC to provide two isomers, which were temporarily assigned as EXAMPLE 203A and EXAMPLE 203B, respectively.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=[O:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1.CCOCC.CCCCCC>[CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([C:16]1[CH:17]=[N:18][CH:19]=[N:20][CH:21]=1)([OH:12])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Brc1cncnc1
Reactant: CC(C)(C)C(=O)COc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(O)(COc1ccccc1)c1cncnc1
Temperature: -110 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
A solution of 19.2 g (0.1 mol) of 3,3-dimethyl-1-phenoxy-butan-2-one in 110 ml of absolute tetrahydrofuran and 70 ml of absolute ether was cooled to -120° C. under a dry nitrogen atmosphere. A solution of 15.7 g (0.1 mol) of 5-bromopyrimidine in 50 ml of absolute tetrahydrofuran was added dropwise. 60 ml of a 15% strength solution of n-butyl-lithium (containing about 0.14 mol) in n-hexane were then slowly added dropwise at -120° C. The mixture was stirred further, first for 2 hours at a temperature of about -110° C. and then overnight at -78° C. The reaction mixture was then warmed to room temperature, mixed with 100 ml of 10% strength ammonium chloride solution and concentrated in vacuo. The aqueous suspension was then extracted with ethyl acetate. The ethyl acetate extract was washed successively twice with 1N hydrochloric acid, twice with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was recrystallized from cyclohexane. 10.5 g (39% of theory) of 3,3-dimethyl-1-phenoxy-2-pyrimidin-5-yl-butan-2-ol of melting point 127°-129° C. were obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>O1CCOCC1>[O:35]1[CH2:34][CH:33]=[C:32]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]3)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=2)[CH2:37][CH2:36]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC1CCN(c2nc(Br)ccc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC1CCN(c2nc(C3=CCOCC3)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C

Procedure:
A mixture of 6′-bromo-4-methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (as prepared in Example 61, step (a)) (237 mg, 0.79 mmol), anhydrous K2CO3 (311 mg, 2.25 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (Murata, M., Synthesis, 778, (2000)) (157 mg, 0.750 mmol) in dioxane (5 mL) was heated at 80° C. overnight under Ar. The reaction mixture was allowed to cool to RT, concentrated and the resulting residue was purified on silica (10% EtOAc/hexane) to obtain the expected coupled compound (71 mg, 30%). 1H-NMR (CDCl3; 400 MHz): δ 8.15 (d, 1H, J=8.4 Hz), 6.80 (m, 2H), 4.39 (m, 2H), 3.92 (t, 2H, J=5.4 Hz), 3.76 (m, 2H), 3.04 (m, 2H), 2.62 (m, 2H), 1.67 (m, 3H), 1.33 (m, 2H), 0.99 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][C:12]=2[CH3:21])=[CH:7][CH:6]=1>C(O)(=O)C>[Br:1][C:10]1[CH:9]=[C:8]([C:11]2[S:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)cc2)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(C)c(-c2ccc(OC)c(Br)c2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Liquid bromine (1.04 g, 0.36 ml, 6.49 mmol) was added to a stirred solution of ethyl 5-(4-methoxyphenyl)-4-methylthiazole-2-carboxylate (prepared according to the procedure reported in WO 2006/089076, 1.5 g, 5.41 mmol) in acetic acid (15 ml) at 25° C. The resulting reaction mixture was then stirred at 25° C. for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The residue obtained after concentration was dissolved in ethyl acetate (100 ml). The mixture obtained was washed with saturated sodium bicarbonate solution (30 ml). The separated organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound 8a (1.70 g, 88.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.C1C(=O)N([I:24])C(=O)C1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([I:24])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccccc1-c1ccc2[nH]ccc2n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccccc1-c1ccc2[nH]cc(I)c2n1
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 5-(2-fluorophenyl)-1H-pyrrolo[3,2-b]pyridine (199 mg, 0.938 mmol) in THF (10 mL) was treated with n-iodosuccinimide (232 mg, 1.031 mmol, Alfa-Aesar). The reaction was stirred at 23° C. under N2. After 45 min, the solution was diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-30% EtOAc/hexane), affording 5-(2-fluorophenyl)-3-iodo-1H-pyrrolo[3,2-b]pyridine (231 mg, 73%). MS (ESI, pos. ion) m/z: 339.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[F:54]C1C=CC(C(B2OC(C)(C)C(C)(C)O2)=C)=CC=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:54])=[CH:27][CH:26]=2)=[CH2:24])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccc(F)cc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: C=C(c1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 92 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 2-(1-(4-fluorophenyl)ethenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 92% yield.
Reaction SMILES: CO.[NH2:3][C:4]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:5]=1[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[CH3:28][C:29]([CH3:33])([CH3:32])[CH:30]=O.C([BH3-])#N.[Na+]>C(OC(=O)C)C.C(O)(=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:4]([NH:3][CH2:28][C:29]([CH3:33])([CH3:32])[CH3:30])=[C:5]([CH:23]=1)[CH:6]([OH:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1C(O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1ccccc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a methanol (5 ml) solution of 2-amino-5-chloro-α-(2-tert-butoxycarbonylaminomethylphenyl)benzyl alcohol (0.5 g) were added trimethyl acetaldehyde (132 mg) and acetic acid (92 mg). The mixture was stirred for 10 minutes at room temperature, to which was added sodium cyano borohydride (97 mg), followed by stirring for one hour at room temperature. To the reaction mixture was added acetic acid ethyl ester (50 ml). The mixture was washed with water and dried over anhydrous Na2SO4. The solvent was then distilled off. The residue was purified by means of a silica gel column chromatography to give the object 5-chloro-α-(2-tert-butoxycarbonylaminomethylphenyl)-2-neopentylaminobenzyl alcohol (0.61 g) as a colorless oily product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21][C@:20]2([F:28])[C:24]([O:26][CH3:27])=[O:25])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.C(Cl)Cl.CO.[Pd]>[F:28][C@:20]1([C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22][CH2:23][C@H:19]1[NH:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1)(=[O:16])=[O:17]
Reactant: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(F)CCC[C@H]1NS(=O)(=O)c1ccc(O)cc1
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of methyl (1R,2R)-2-({[4-(benzyloxy)phenyl]sulfonyl}amino)-1-fluorocyclopentanecarboxylate in EtOAc/CH2Cl2/MeOH (5 mL/2 mL/10 mL) was added 10% Pd/C (0.14 g). The reaction vessel was purged with nitrogen followed by hydrogen. The reaction was stirred for 1 h under 1 atmosphere of hydrogen, and then filtered through celite and concentrated to afford methyl (1R,2R)-1-fluoro-2-{[(4-hydroxyphenyl)sulfonyl]amino}cyclopentanecarboxylate as an amorphous solid (0.433 g, 97%). MS: 318.1 (M+H)+.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[C:8]([NH:22][CH2:23][CH2:24][CH3:25])=[N:9][C:10]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[NH2:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)(=O)C>[C:18]([C:17]1[CH:20]=[CH:21][C:14]([NH:13][C:10]2[N:9]=[C:8]([NH:22][CH2:23][CH2:24][CH3:25])[C:7]([C:6]#[C:5][CH2:4][CH2:3][CH2:2][NH:26][C:27]([CH3:39])([CH3:38])[CH2:28][N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[CH:12][N:11]=2)=[CH:15][CH:16]=1)#[N:19]
Reactant: CN(CC(C)(C)N)C(=O)OC(C)(C)C
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCNC(C)(C)CN(C)C(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 4-((5-(5-oxo-1-pentyn-1-yl)-4-(propylamino)pyrimidin-2-yl)amino)benzonitrile (G12, 300 mg) and tert-butyl (2-amino-2-methylpropyl)(methyl)carbamate (G10, 112 mg) in methylene chloride (4 mL), sodium triacetoxyborohydride (195 mg) and acetic acid (21 μL) were added at room temperature, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium hydrogencarbonate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol) to obtain tert-butyl (2-((5-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-2-methylpropyl)(methyl)carbamate (G13, 80 mg).