Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=NO)[C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(#[N:30])C>[Pd]>[NH2:30][N:1]=[CH:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C(N)=NO)c2)cc1
Reactant: CC#N
Agent: [Pd]
Product: CCOC(=O)CCc1ccc(CNC(=O)c2cccc(C=NN)c2)cc1

Procedure:
The compound of Example 13 (0.49 g, 1.3 mmol) was dissolved in ACOH and hydrogenated with 4% Pd/C (53% wet, 0.050 g) in a Parr Shaker (60 psi, 60C). The catalyst was filtered off and the filtrate concentrated in vacuo to give a white solid. The solid was slurried with acetonitrile and the resulting white solid was collected by vacuum filtration (0.423 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH:9]1[O:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[Ca+2]>COCCOC>[CH2:8]([O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23])[CH:9]1[O:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(Cl)OCCCl
Reactant: Nc1ccc(OCC2CCCO2)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOC
Product: O=C(Nc1ccc(OCC2CCCO2)c([N+](=O)[O-])c1)OCCCl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
36 g of β-chloroethyl chloroformate are added dropwise to 59.5 g of 4-amino-2-nitrophenyl tetrahydrofurfuryl ether of the formula V (obtainable according to A.1. or A.2.) and 14 g of calcium carbonate in 200 ml of 1,2-dimethoxyethane at 70° C. The mixture is then stirred at 80° C. for 1 hour, the inorganic salts are removed at elevated temperature, and the filtrate is evaporated to dryness. The remaining oil completely crystallizes after a short time; the crystals are triturated with 50 ml of ether, filtered off with suction, washed with a little ether, and dried. 75.8 g (88% of the theoretical figure) of 4-(β-chloroethoxycarbonyl)amino-2-nitrophenyl tetrahydrofurfuryl ether are obtained with a melting point of 84°-86° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][S:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:31][CH:30]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 84.4 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (399 mg, 1.65 mmol) and 4-methylsulfonylbenzoic acid (463 mg, 2.31 mmol) yielded 591 mg (84%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1>CN(C=O)C>[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38]([NH:1][C:2]3[CH:3]=[C:4]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=5)[N:13]=4)[CH:5]=[CH:6][CH:7]=3)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5cnccc45)c3)ccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(3-aminophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 5) (0.032 g, 0.12 mmol), DMF (2.0 mL), pyridine (0.015 mL, 0.180 mmol), and isoquinoline-5-sulfonyl chloride hydrochloride (0.0395 g, 0.150 mmol, Toronto Research Chemicals, Ottawa, Ontario). The mixture was stirred at 25° C. for 5 h then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) to afford the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 459 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.03 (s, 1H), 10.91 (s, 1H), 9.50 (s, 1H), 8.75 (d, J=6.5 Hz, 1H), 8.58 (d, J=6.0 Hz, 1H), 8.53 (d, J=7.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.25 (s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([C:15]([O:17][CH3:20])=[O:16])=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CSc2ccncc2C(=O)O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cnccc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2.2 g (0.008 mole) of 4-(4-methoxybenzylthio)-nicotinic acid in 30 mL of dry N,N-dimethylformamide was reacted with 1.78 g (0.011 mole) of 1,1'-carbonyldiimidazole. This was stirred at room temperature for 2 hours, then 0.5 mL of 4.3M sodium methoxide in methanol and 5 mL of methanol. The reaction was stirred for 1 hour at room temperature, then partitioned between 75 mL of ether and 30 mL of water. The ether layer was extracted with 2×30 mL of water, dried, concentrated to a small volume, and hexane added to crystallize methyl 4-(4-methoxybenzylthio) nicotinate; yield 1.66 g (72% of theory), m.p. 108°-110° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH:24]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH2:25].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[N:7]([CH2:8][CH2:9][O:10][C:4]4[CH:3]=[C:2](/[CH:25]=[CH:24]/[S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:5]=43)[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: C=CS(N)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(/C=C/S(N)(=O)=O)cc1OCC2
Temperature: 130 °C
Yield: 35.2 %

Procedure:
8-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene 194 (400 mg, 1.07 mmol), ethenesulfonic acid amide (172 mg, 1.60 mmol), triethylamine (223 μL, 1.60 mmol), tri-o-tolyl-phosphane (65 mg, 0.21 mmol) and palladium (II) acetate (12 mg, 0.05 mmol) were suspended in DMF (5 mL) and the reaction mixture degassed by bubbling argon through the suspension. The reaction mixture was heated at 130° C. for 16 h, before cooling to RT and diluting the mixture with ethyl acetate (10 mL). The resultant mixture was washed with water, extracted with ethyl acetate (2×10 mL) and the combined organic extracts washed with brine, dried (MgSO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in DCM) to yield the title compound as a white solid (151 mg, 35%) LCMS: RT=2.69 min, [M+H]+=401.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15]I.[CH3:17][CH2:18][C:19](=[O:25])[CH2:20][C:21](=[O:24])[CH2:22][CH3:23].[Li]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:20]([C:19](=[O:25])[CH2:18][CH3:17])[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: COc1cc(Cl)ccc1C=CCCCCI
Reactant: CCC(=O)CC(=O)CC
Agent: [Li]
Product: CCC(=O)C(CCCCC=Cc1ccc(Cl)cc1OC)C(=O)CC

Procedure:
4-[6-(2-Methoxy-4-chlorophenyl)-5-hexenyl] -3,5-heptanedione was prepared from 84 g. of 6-(2-methoxy-4-chlorophenyl)-5-hexenyl iodide and lithium 3,5-heptanedione (from 42 g. of 3,5-heptanedione and 2.6 g. of lithium hydride in 400 ml. of dimethylformamide). The product was chromatographed on silica gel and eluted with ethyl acetate-hexane 1:4 to give 56 g. of oil used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:30]#[N:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-:32].[Na+].Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:30]([NH2:31])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: [OH-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCCCC3)s2)c1
Agent: Cl
Agent: [Na+]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCCCC3)s2)c1
Temperature: 100 °C
Yield: 8.7 %

Procedure:
A mixture of 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarbonitrile (45 mg, 0.10 mmol) and NaOH (1M in MeOH, 0.5 ml, 0.50 mmol) was heated at 100° C. in the microwave for 16 hrs. The mixture was brought to pH=3 by addition of HCl (1.0 N in H2O) and then partitioned between EtOAc (5 mL) and brine (5 mL). The organic layer was separated, dried (Na2SO4), filtered and the volatiles were removed under reduced pressure. The residue was purified by HPLC (gradient elution 40% to 100% CH3CN in H2O/0.1% TFA, 20 mins, 20 ml/min) to give the title compound (4.0 mg, 8.67 μmol, 8.5% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:25][CH:24]([OH:26])[CH2:23]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=[O:39]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:23][C:24]([OH:39])([OH:26])[CH2:25]4)[CH:17]=3)[N:12]([CH3:27])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)C3)ccc21
Reactant: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CC(O)(O)C3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(4-chlorobenzyl)-6-[(3-hydroxy-1-azetidinyl)methyl]-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.10 gm) from Example No. 75 in dry DMSO (3 mL) containing triethylamine (0.35 mL) is treated with pyridine-sulfar trioxide complex (0.25 gm). The reaction mixture is stirred at room temperature for 2 hrs. The reaction mixture is diluted with ethyl acetate and washed with water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is purified by recrysrallization from acetonitrile to afford 0.06 gm of the title compound as a tan solid.
Reaction SMILES: CN1CCOCC1.C(OC(Cl)=O)C(C)C.[F:16][C:17]1[N:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[CH:19][CH:18]=1.Cl.[CH3:27][O:28][NH:29][CH3:30]>C(Cl)Cl>[CH3:27][O:28][N:29]([CH3:30])[C:23]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[N:22]=1)=[O:25]
Reactant: CNOC
Reactant: O=C(O)c1cccc(F)n1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)n1
Reaction time: 17 h
Yield: 19.6 %

Procedure:
Add N-methylmorpholine (6 mL, 52 mmol) and isobutylchloroformate (3.5 mL, 26.9 mmol) to a solution of 6-fluoropyridine-2-carboxylic acid (3.8 g, 26.9 mmol) in methylene chloride at 0° C. After 15 minutes add O,N-dimethylhydroxylamine hydrochloride (2.6 g, 26.9 mmol) and N-methylmorpholine (3 mL, 26.9 mmol). Stir the reaction at 0° C. for 15 minutes and then room temperature for 17 hours. Dilute the reaction with methylene chloride and wash sequentially with water (1×50 mL), 10% aqueous citric acid (1×50 mL), brine (1×50 mL), saturated aqueous sodium bicarbonate (1×50 mL), and brine (1×50 mL). Dry the resulting organic solution with Na2SO4, filter, and purify by flash column chromatography (Silica Gel, 20% acetone/hexanes) to provide the title compound 0.97 g (18% from 2-fluoro-5-methylpyridine) as a clear, yellow oil.
Reaction SMILES: [Li]CCCC.Br[C:7]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:14][C:10]2[O:11][CH2:12][O:13][C:9]=2[CH:8]=1.C[O:24][B:25](OC)[O:26]C.[OH-].[Na+]>C1COCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:7]([B:25]([OH:26])[OH:24])=[CH:8][C:9]3[O:13][CH2:12][O:11][C:10]=3[CH:14]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(-c2cc3c(cc2Br)OCO3)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OB(O)c1cc2c(cc1-c1ccc(F)cc1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Under nitrogen, 6.3 mL (15.8 mmol) of n-BuLi (2.5M in hexanes) was added to a stirred solution of 3.9 g (13.2 mmol) of 5-bromo-6-(4-fluorophenyl)-1,3-benzodioxole (Step 1) in 30 mL of anhydrous THF at -78° C. After 30 minutes, 4.5 mL (39.4 mmol) of trimethylborate was added. The reaction was warmed to ambient temperature and stirred for 3 hours prior to the addition of 60 mL of 5% NaOH. The reaction was stirred for an additional 60 minutes, the THF removed in vacuo, and the pH adjusted to ca. 4. The residue was dissolved in ethyl acetate; the resulting solution was dried over Na2S04 and concentrated in vacuo to give 1.7 g (50%) of [6 (4-fluorophenyl)-1,3-benzodioxol-5-yl] boronic acid as a pale yellow solid: NMR (CDCl3) δ 4.00 (br s, 2H), 6.06 (s, 2H), 6.75 (s, 1H), 7.08-7.17 (m, 2H), 7.26 (s, 1H), 7.31-7.39 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:8]([NH:10][C:11]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN(CCN(C)C)C.CN([CH:36]=[O:37])C>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:7]2[C:6]=1[CH:36]([OH:37])[N:10]([C:11]([CH3:19])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:12])[C:8]2=[O:9]
Reactant: CN(C)C=O
Reactant: COCOc1cc(C(=O)NC(C)(C)c2ccccc2)ccc1OC
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: COCOc1c(OC)ccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 78.7 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-methoxymethoxy-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (7.50 g, 22.8 mmol) was dissolved in THF (200-mL), and the solution was treated with TMEDA (11.0 mL, 72.9 mmol), sec-butyl lithium-hexane solution (0.95 mol/L, 77.0 mL, 73.2 mmol) and DMF (3.88 mL, 50.1 mmol), followed by purification by slurry using isopropylether and hexane to obtain 4-methoxymethoxy-5-methoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (6.41 g, yield 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[CH2:11][CH3:12].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=[O:13])[C:11](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CCC(=O)c1cc(C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C)cc1C(=O)C(C)=Cc1ccccc1
Yield: 101.3 %

Procedure:
To a mixture of 140 g of 2'-methoxy-5'-methylpropiophenone, 83.4 g of benzaldehyde and 1.5 liters of ethanol was added 154 ml of 20%-sodium hydroxide aqueous solution under stirring. The reaction mixture was stirred overnight at room temperature, then 10%-hydrochloric acid was added to make the reaction mixture acidic, and extracted with benzene. The benzene extract was washed with water and an aqueous solution saturated with sodium chloride in this order, then dried to obtain 212 g of 2'-methoxy-5'-methyl-2-benzylidenepropiophenone. Yellow oily substance.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@H:15]([C:16]([OH:18])=O)[C@@H:14]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:13][N:12]2C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH2:35]([OH:37])[CH3:36]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[C@H:15]([C:16]([O:37][CH2:35][CH3:36])=[O:18])[C@@H:14]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:13][NH:12]2)=[CH:9][CH:10]=1)[CH2:2][CH3:3]
Reactant: CCO
Reactant: CCCOc1ccc([C@H]2[C@H](C(=O)O)[C@@H](c3ccc4c(c3)OCO4)CN2C(=O)OC(C)(C)C)cc1
Product: CCCOc1ccc([C@@H]2NC[C@H](c3ccc4c(c3)OCO4)[C@H]2C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of Example 20A was dissolved in ethanol and cooled in an ice bath. Gaseous HCl was bubbled through the solution until saturated; the resultant solution was warmed to ambient temperature and allowed to stir overnight under a blanket of nitrogen. The solvents were removed in vacuo; the residue was taken up in bicarb and extracted with EtOAc. The organic layer was decanted, then washed with brine and dried over Na2SO4.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44].C(O)(=O)C.[BH4-].[Na+]>CO>[OH:38][CH2:39][CH2:40][N:41]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:20]2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=[C:18]([C:14]3[C:13]([CH3:35])=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:37][CH:36]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=2)=[CH:28][CH:29]=1)[CH2:42][CH2:43][OH:44]
Reactant: OCCNCCO
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C=O)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CN(CCO)CCO)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (4) (110 mg; 0.22 mmol) was dissolved in methanol (10 mL) and 1 mL 2-(2-hydroxy-ethylamino)-ethanol was added. To the stirring reaction solution was then added 0.25 mL glacial acetic acid, followed by 0.25 g powdered molecular sieves (4 Å; activated) and the resulting slurry allowed to stir at rt for 4 hr under N2, then heated to 50° C. After 3 hr at 50° C., the reaction was cooled to rt and excess NaBH4 powder (0.5 g) was added portionwise to the stirring slurry. After gas evolution ceased, the reaction slurry was then adsorbed directly onto silica gel and was chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide N-{3-[6-(4-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (5) (75 mg) as an off-white solid. MS 584.24 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2N3C=C(C4C=CC=CC=4N)N=C3SC=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[N:40]=[C:41]2[N:45]([CH:46]=1)[CH:44]=[C:43]([CH2:47]O)[S:42]2)([O-])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:47][C:43]2[S:42][C:41]3=[N:40][C:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[NH2:30])=[CH:46][N:45]3[CH:44]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccccc1-c1cn2cc(CO)sc2n1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2csc3nc(-c4ccccc4N)cn23)CC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn3cc(-c4ccccc4N)nc3s2)CC1

Procedure:
Essentially the same procedure used during the preparation of 4-[6-(2-amino-phenyl)-imidazo[2,1-b]thiazol-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester was employed, except that [6-(2-nitro-phenyl)-imidazo[2,1-b]thiazol-2-yl]-methanol was used as the starting material.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[OH:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>CN(C=O)C>[OH:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2](=[O:3])[O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)cc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
4.3 g (0.02 mol) of 2,2,2-trichloroethyl chloroformate are dissolved in 20 ml of DMF and added dropwise to a solution of 10.9 g (0.1 mol) of 4-hydroxyaniline in 100 ml of DMF. After the mixture has been stirred for a further hour at room temperature, it is poured into ice water, acidified and filtered with suction, and the material filtered off is washed with water. The product is recrystallized from toluene using activated charcoal.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C@@H:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:25]Br)=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[CH:18]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[N:1]([CH2:25][C@@H:24]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:23])[NH:21]2)[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 80 °C
Yield: 148.3 %

Procedure:
NaN3 (266 mg, 4.1 mmol) was added to a stirred solution of (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsilyl)oxy]ethyl]quinolin-2(1H)-one (1 g, 2.05 mmol) in DMF (20 mL) at rt and warmed to 80° C. for 3 h. The resulting solution was poured into H2O (80 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give the title compound (1.37 g) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C24H31N4O3Si+ 451.2. found m/z=451.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH2:19]1[O:28][C:27]2[CH:26]=[CH:25][C:23](N)=[CH:22][C:21]=2[O:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:20]1[C:21]2[CH:22]=[CH:23][C:25]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][C:27]=2[O:28][CH2:19]1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCO5)c3c2s1
Yield: 49 %

Procedure:
Prepared from VII and 3,4-(methylenedioxy)aniline. Flash chromatography eluent (DCM-EtOAc, 9:1). Yield: 49%; orange solid; mp>260° C.; IR (KBr) νmax/cm−1 2894, 2226, 1734, 1706, 1645, 1609, 1581, 1555, 1499, 1471, 1377, 1354, 1304, 1264, 1236, 1211, 1188, 1162, 1125, 1086, 1037, 972, 938, 924, 859, 829, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.14 (m, 1H), 7.76 (m, 1H), 6.94 (d, 2H, J=9.0 Hz), 6.72 (m, 1H), 6.02 (s, 2H); HRMS calcd for C17H9N5O2S (M+H+): 348.0555, found 348.0566.