Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2ccccc2Br)cc1
Yield: 82.5 %

Procedure:
Under nitrogen, 1.2 g (1.0 mmol) of Pd(PPh3)4 was added to a stirred solution of 9.9 g (42 mmol) of 1,2-dibromobenzene (Aldrich) and 3.0 g (21 mmol) of 4-fluorophenylboronic acid in 42 mL of toluene, 42 mL of ethanol and 42 mL of 2M Na2CO3. After vigorous stirring at reflux for 3 hours, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was washed with water and dried over MgSO4. Purification by silica gel chromatography (Waters Prep-500A) with hexane gave 4.35 g (81%) of 1-bromo-2-(4-fluorophenyl)benzene as a colorless oil: NMR (CDCl3) δ 7.07-7.26 (m, 3H), 7.27-7.44 (m, 4H), 7.67 (d, J=8 Hz, 1H).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(Cl)Cl>[C:16]([NH:20][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Powdered isoquinoline-5-sulfonyl chloride hydrochloride (1.00 g, 3.79 mmol) is added in small portions to a stirred solution of tert-butylamine (2.00 mL, 18.9 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 1 hour. Ethyl acetate (50 mL) is added to the mixture and the mixture is washed with saturated aqueous NaHCO3 (20 mL). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% CH3OH in CH2Cl2) to give 857 mg (3.24 mmol, 86% yield) of the title compound as a white solid. ESIMS: m/z 265 (M+H)+. Analysis for C13H16N2O2S: calcd: C, 59.07; H, 6.10; N, 10.60; found: C, 59.21; H, 6.01; N, 10.67.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][C@H:19]5[C:20]([O:26]C)=[CH:21][CH:22]=[C:23]2[C@:11]5([C:12]=34)[CH2:10][CH2:9]1.[OH-].[Na+]>O.C(O)(=O)C.OO>[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][CH:19]5[C:20]([CH:21]=[CH:22][C@:23]2([OH:3])[C@:11]5([C:12]=34)[CH2:10][CH2:9]1)=[O:26]
Reactant: O=C(O)C(=O)O
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 2 °C
Yield: 82 %

Procedure:
6-Benzyloxy-4,5α-epoxy-3-methoxy-17-methylmorfina-6,8(14)-diene (52.5 g) is dissolved in a solution prepared by dissolving 9.8 g of oxalic acid in 35 ml of water, 10 ml of acetic acid and 21.2 ml of 30% hydrogen peroxide are added. The reaction mixture is stirred at 20° C. until total conversion of the benzyl analogue of thebaine, the reaction mixture is cooled down to 2° C., 8% aqueous solution of NaOH is added with stirring until pH of 9.2. Precipitated crystals of 14-hydroxycodeinone are filtered off, washed with water and dried. The procedure yields ca. 37 g of 14-hydroxycodeinone (82%). Further procedure of preparation of Oxycodone hydrochloride is the same as in Example Ib) and Ic).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][NH:17][CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[F:42][C:43]1[CH:44]=[N:45][C:46](Cl)=[N:47][CH:48]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:46]3[N:47]=[CH:48][C:43]([F:42])=[CH:44][N:45]=3)[CH2:16][C@:14]2([C:19]2[CH:20]=[C:21]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CNC[C@H]2CS1)c1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=N[C@@]2(c3cccc(NC(=O)c4ccc(F)cn4)c3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 50 °C
Yield: 41 %

Procedure:
A solution of N-[3-[(4aR,7aS)-2-benzamido-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-fluoro-pyridine-2-carboxamide; 2,2,2-trifluoroacetic acid (150 mg, 254 μmol), 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is heated in dimethyl sulfoxide (5 mL) overnight at 40° C. Additional 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is added and the mixture is heated overnight at 50° C. Additional 5-fluoro-2-chloropyrimidine (68 mg, 51 μmol) and diisopropylethylamine (98 μL, 56 μmol) is added and the mixture is heated overnight at 50° C. for a third night. The reaction is cooled, diluted with saturated aqueous sodium carbonate (50 mL) to give a slurry that is filtered and dried in a vacuum oven at 50° C. for 4 hours to give the title compound (60 mg, 41%). ES/MS (m/e): 449 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].[CH:19]([Sn](CCCC)(CCCC)CCCC)=[CH2:20].CCOC(C)=O.O>CS(C)=O>[C:12]1([C:7]2[NH:8][C:9]3[C:4]([C:5](=[O:18])[CH:6]=2)=[CH:3][C:2]([CH:19]=[CH2:20])=[CH:11][CH:10]=3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1cc(-c2ccccc2)[nH]c2ccc(Br)cc12
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a solution of 6-bromo-2-phenylquinolin-4(1H)-one 1 (1.5 g, 5.0 mmol) in DMSO (60 mL) was added vinyltributyl tin (1.75 mL, 6.0 mmol) and tetrakis-triphenylphosphine palladium (116 mg, 0.1 mmol). The mixture was then heated to 100° C. for 20 h, at which time, LC-MS revealed the disappearance of starting material. The reaction was then poured into a mixture of EtOAc (200 mL) and water (400 mL) which caused a grayish solid to precipitate. This solid was collected and dried under vacuum in a desiccator over night to yield 1.21 g (97% yield) of 2-phenyl-6-vinylquinolin-4(1H)-one which was pure by 1H NMR and LC-MS. 1H NMR (400 MHz, DMSO-d6) ppm: 11.75 (br s, 1H), 8.08 (s, 1H), 7.85 (m, 3H), 7.74 (d, J=8.8 Hz, 1H), 7.59 (m, 3H), 6.88 (dd, J=17.6 Hz, 10.8 Hz, 1H), 6.34 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.30 (d, J=10.8 Hz, 1H). LRMS (CI, [M+H]) Calc'd=248.2. found=248.2. HRMS (APCI, [M+H]+) Calc'd for C15H11BrNO: 248.1070. found: 248.1068.
Reaction SMILES: [CH3:1][CH:2]([NH2:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:20])([F:19])[C:10]([F:18])([F:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:22]([O:24]C=O)C>>[CH3:1][CH:2]([NH:21][CH:22]=[O:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:19])([F:20])[C:10]([F:17])([F:18])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC=O
Reactant: CC(N)c1ccccc1C(F)(F)C(F)(F)c1ccccc1
Product: CC(NC=O)c1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
α-Methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzylamine, 1.06 g. (0.00357 mole), in 50 ml. of ethylformate is stirred and heated to refluxing for about 21 hours. Evaporation of the solution to dryness and trituration of the residue with hexane gives N-[α-methyl-2-(α,α,β,β-tetrafluorophenethyl)-benzyl]-formamide, m.p. 94.5°-99° C. Recrystallizations from ether-petroleum ether and isopropyl alcohol-water afford a purified sample, m.p. 103°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([S:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)(=[O:27])=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(F)cc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (0.25 g, 1.0 mmol), 4-fluorobenzenesulfonyl chloride (0.23 g, 1.2 mmol), and triethylamine (349 μL, 2.5 mmol) are stirred at room temp. for 15 h. The reaction mixture is diluted with EtOAc, washed with water, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding the title product as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]([C:21]1[C:22]([O:33][CH3:34])=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25][CH:26]=1)=[CH2:20])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:19]([C:21]2[C:22]([O:33][CH3:34])=[C:23]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2ccccc2)c1OC)c1cccc(C(C)(C)C)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1c(-c2ccccc2)cccc1C(C)c1cccc(C(C)(C)C)c1O
Temperature: 65 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
A solution of 12 (1.05 g, 2.34 mmol) in methanol (30 mL) and ethyl acetate (60 mL) was treated with 20% palladium on activated carbon (50% wet, 0.10 g) and was hydrogenated at 30 psi in a Parr shaker for 16 hr. The catalyst was filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the crude product was purified by chromatography on silica (80 g) with 1% ethyl acetate in hexane (3 L). The relevant fractions were stripped and the residue was taken up in ethanol (10 mL) and stirred at 65° C. for 30 min. The resulting slurry was allowed to cool overnight. The crystals were collected by filtration, washed with cold ethanol and dried in a vacuum oven at 65° C. to produce pure B3 (0.29 g, 35%).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][CH:6]=[CH:7][C:8](=[O:10])[CH3:9].FC(F)(F)C(O)=O.O>C(OCC)C>[O:10]=[C:8]([CH3:9])[CH:7]=[CH:6][S:5][CH2:4][CH:3]=[O:2]
Reactant: COC(CSC=CC(C)=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: CC(=O)C=CSCC=O

Procedure:
A solution of 3.0 g. (15.7 mmol) of (3-oxo-1-butenyl)mercaptoacetaldehyde dimethylacetal in 30 ml. of 10:1 trifluoroacetic acid/water at 0° was stirred 2 hours, poured into 150 ml. of water and extracted with CHCl3 (4×50 ml.). The CHCl3 was washed with cold aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and stripped in vacuo to afford 2.1 g. (93%) of the crude mixture of aldeyde double bond isomers (68:32::E to Z). Column chromatography on silica gel using ethyl ether as eluent afforded both isomers in a ratio of 4:1::E:Z. The (Z-3-oxo-1-butenyl)mercaptoacetaldehyde eluted first: Rf 0.45, 1H-NMR (CDCl3) delta 2.25 (s, 3), 3.45 (d, 2, J=3.2 Hz), 6.38 (d, 1, J=9.8 Hz), 6.80 (d, 1, J=9.8 Hz), 9.62 (t, 1, J= 3.2 Hz); IR (KBr) cm-1 1721 (m), 1659 (s); mass spectrum (70 eV) m/e 144.0240 (parent, calcd. for C6H8O2S; 144.0354), 126.0130 (p--H2O, calcd. for C6H6OS; 126.0198), 115.0230 (p--CHO), 97 (p--CHO and --OH2). The Eolefin isomer (Rf 0.3) exhibited the following spectral characteristics: 1H-NMR (CDCl3) delta 1.94 (s, 3), 3.38 (d, 2, J=3.2 Hz), 5.85 (d, 1, J=15.9 Hz), 7.24 (d, 1, J=15.9 Hz), 9.35 (t, 1, J=3.2 Hz); IR (film) cm-1 1724 (m), 1660 (s); mass spectrum (70 eV) m/e 144.0242 (parent, calcd. for C6H8O2S: 144.0354), 101.0053 (base, p--CH2CHO, calcd. for C4H5Os; 101.0120 ).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C@H:36]([C:37]([O-:39])=O)[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:75]([O:82][C:83](=[O:86])[CH2:84][NH2:85])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:25]([N:28]1[C@H:36]([C:37]([NH:85][CH2:84][C:83]([O:82][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:86])=[O:39])[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
PyBroP (233 mg, 0.5 mmol) was added to a solution of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate (264 mg, 0.5 mmol), glycine benzyl ester p-toluenesulphonate (170 mg, 0.5 mmol) and diisopropylethylamine (260 μl, 1.5 mmol in dry DCM (5 ml). The reaction mixture was stirred at room temperature for 18 hours, diluted with DCM (20 ml), washed successively with 2N HCl solution (25 ml), brine (25 ml) and dried (MgSO4). Filtration an evaporation of the solvent gave the crude product (350 mg) which was purified by flash chromatography on silica gel with ethyl acetate-DCM (3:7) as eluant, affording the product as a colourless oil. (190 mg, 55%).
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N:16]#[C:17]Br>CCOCC>[CH2:9]([N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]1=[N:2][C:17]#[N:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N#CBr
Reactant: Nc1cccc[n+]1Cc1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: N#CN=c1ccccn1Cc1ccccc1
Yield: 43.5 %

Procedure:
5.3 g (20 mmole) of 2-amino-1-benzylpyridinium bromide [prepared according to Chem. Ber. 88, 1103 (1955)] are suspended in 20 ml of ether, then 20 ml of aqueous sodium hydroxide solution of 0.5 mole/liter concentration are added while stirring. After the dissolution of the solid phase the phases are separated and the aqueous phase is extracted with 20 ml of ether. The combined organic phase is dried over anhydrous sodium sulfate and evaporated to its half volume under reduced pressure. Then, a solution containing 1.1 g (10 mmole) of cyanogen bromide in 5 ml of ether is dropped to the ethereal solution at room temperature under stirring. After stirring for 30 minutes the crystalline precipitate is filtered, washed with ether and then with a great volume of water, then the product is dried in air to yield 0.91 g (44%) of the named product, m.p.: 139°-140° C. (after recrystallization from ethanol the melting point raises to 147°-148° C.). On the basis of its melting point, infrared spectrum and thin layer chromatography (TLC) characteristics, this product proved to be indentical to the target compound of Example 2.
Reaction SMILES: C[CH:2]([C:9]1NC2[C:16]([C:17]=1[S:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[CH:12]=2)[C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH3:36].CN(P([N:45]([CH3:47])[CH3:46])(N(C)C)=O)C>C1COCC1.C1(C)C=CC=CC=1>[CH3:46][N:45]1[C:47]2[C:16](=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[CH:12]=2)[C:17]([S:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:9]1[CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH3:36])=[O:5]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CI
Reactant: COc1ccc2c(SC(C)(C)C)c(C(C)C(C)(C)C(=O)O)[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2ccc(OC)cc2n1C
Reaction time: 0.25 h

Procedure:
A solution of 1.75 g of the indole from Step A in 30 mL of THF and 3 mL HMPA was cooled to -78° C. and to this solution was slowly added a solution of 0.54M KHMDS in toluene (10.2 mL). The mixture was stirred at this temperature for 15 min. and treated with 0.34 mL of iodomethane. The mixture was stirred at -78° C. for 5 h, quenched with 1N HC1 (100 mL), extracted with ethyl acetate, and the organic layer washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as eluant to afford the title compound as a solid; m.p. 97-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](O)[C:8]([CH3:13])=[N:7]2.P(Cl)(Cl)([Cl:16])=O>[NH4+].[OH-]>[Cl:16][C:9]1[C:8]([CH3:13])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2cccc(Cl)c2nc1O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2cccc(Cl)c2nc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 8-chloro-3-methylquinoxalin-2-ol (1.0765 g, 5.5314 mmol) and phosphorous oxychloride (10.127 mL, 110.63 mmol) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature. The mixture was poured into ice (˜100 mL) with stirring and neutralized with NH4OH (30 mL) and ice with stirring. The resulting precipitate was collected by filtration, rinsed with water (200 mL), and dried to give 3,5-dichloro-2-methylquinoxaline as a pink solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98-8.07 (2H, m), 7.84 (1H, dd, J=8.3, 7.7 Hz), 2.79 (3H, s); LC-MS (ESI) m/z 213.0 [M+H]+. The pink solid was carried on crude without purification for the next step.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]O)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.C(Br)(Br)(Br)[Br:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:32][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([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
Reactant: CC(C)(C)[Si](OCCOCCOCCOCCO)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCOCCOCCOCCBr)(c1ccccc1)c1ccccc1

Procedure:
Compound 10 (651 mg, 1.50 mmol) and carbon tetrabromide (628 mg, 1.88 mmol) were dissolved in tetrahydrofuran (THF, 0.5 mL). Triphenylphosphine (498 mg, 1.88 mmol) was added to this solution portionwise over 5 min with stirring and additional amount of THF (0.5 mL) was added to the mixture. Reaction was monitored by TLC, which indicated that it was over in 10 min Solvent was removed at room temperature and the crude product was chromatographed (SiO2, hexane/EtOAc 2:1) to give 767 mg (1.55 mmol, >100%, less dry) of 35 as a clear colorless oil. Rf 0.74 (hexane/EtOAc 1:1); 1H NMR (400 MHz, CDCl3) 7.68 (m, 4H, H-2 of phenyl), 7.45-7.35 (m, 6H, H-3 and H-4 of phenyl), 3.81 (t, 2H, J=5.5 Hz, CH2CH2OSi), 3.79 (t, 2H, J=7.1 Hz, CH2CH2Br), 3.65 (m, 8H, (OCH2CH2)2OCH2CH2OSi), 3.61 (t, 2H, J=5.3 Hz, CH2CH2OSi), 3.45 (t, 2H, J=6.4 Hz, CH2CH2Br), 1.05 (s, 9H, C(CH3)3); MS (ESI) Calcd for C24H35BrO4SiNa (M+Na+): 517.1. Found: 517.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:30][C:31]4[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=4)=[O:25])[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Nc2cc(N3CCCC(C(=O)O)C3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCCC(C(=O)Nc4ccc(C(=O)OC(C)(C)C)cc4)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 139.5 %

Procedure:
A mixture of 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxylic acid (100 mg, 0.25 mmol), tert-butyl 4-aminobenzoate (49 mg, 0.25 mmol), EDCI (192 mg, 1.0 mmol) and 1-methyl-1H-imidazole (82 mg, 1.0 mmol) in dichloromethane (3 mL) was stirred at room temperature for 16 h. The residue was concentrated to give crude tert-butyl 4-(1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidine-3-carboxamido)benzoate (200 mg, crude) as brown liquid that was used directly without further purification. LC-MS: 574 [M+1]+, tR=1.720 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[Br:9][C:10]1[CH:11]=[C:12]([CH2:20][CH2:21][CH2:22]N2CCOCC2)[N:13]2[C:18]=1[C:17]([NH2:19])=[N:16][CH:15]=[N:14]2>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:20][CH2:21][CH2:22][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH2:3][O:2][CH3:1])[N:13]2[C:18]=1[C:17]([NH2:19])=[N:16][CH:15]=[N:14]2
Reactant: Nc1ncnn2c(CCCN3CCOCC3)cc(Br)c12
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1CCCc1cc(Br)c2c(N)ncnn12

Procedure:
Intermediate V step 4 (947 mg, 2.8 mmol) was allowed to react with (2S)-2-(methoxymethyl)pyrrolidine (980 mg, 8.5 mmol) using the procedure to make 5-bromo-7-(3-morpholin-4-ylpropyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine. The reaction was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was extracted with EtOAc (10 mL). The combined organic layer was washed with brine (10 mL) then dried with sodium sulfate. The reaction was concentrated under vacuum to quantitatively yield crude product. 1H-NMR (DMSO-d6) 7.83 (s, 1H), 6.61 (s, 1H), 3.25 (m, 1H), 3.19 (s, 3H), 3.12 to 2.72 (m, 6H), 2.23 (m, 1H), 2.04 (m, 1H), 1.77 (m, 3H), 1.62 (m, 2H), 1.40 (m, 1H); MS [M+H]+=622.2; LCMS RT=2.68.