Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:29])[C:27]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=4[O:24][CH3:25])=[N:14][C:13]=3[CH:26]=2)[NH:9][C:8]1=[O:28].C(N(CC)CC)C>CN(C)C=O>[CH3:6][C:7]1([CH3:29])[C:27]2[C:10](=[CH:11][C:12]3[NH:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:19][C:18]=4[O:24][CH3:25])=[N:14][C:13]=3[CH:26]=2)[NH:9][C:8]1=[O:28]
Reactant: COc1cc(O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OS(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Reaction time: 2 h

Procedure:
0.53 g. (4.6 mmol) methanesulphonyl chloride was added dropwise at 25° C. to a solution of 1.5 g. (4.6 mmol) 7,7-dimethyl-2-(2-methoxy-4-hydroxyphenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one and 0.46 g. (4.6 mmol) triethylamine in 20 ml. dimethylformamide. After 2 hours, the dimethylformamide was distilled off in a vacuum. The residue was worked up with water and filtered off with suction. The residue was recrystallised from ethanol. There were obtained 1.3 g. (70.6% of theory) of the title compound; m.p. 233°-235° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (2.59 g) in dichloromethane (45 mL) was treated with trifluoroacetic acid (8.6 g) followed by triethylsilane (17.5 g). The resulting brown reaction mixture was stirred for 5 minutes and then poured into a saturated solution of sodium bicarbonate. The bicarbonate solution was extracted with dichloromethane. The dichloromethane solution was dried and evaporated to give the des-hydroxy compound (2.1 g); NMR (CDCl3): 1.55-1.66 (m, 2), 1.78-1.82 (br, 2), 2.91, (m, 2), 3.11 (m, 1), 3.8 and 3.82 (s, 3), 4.32 (br, 2), 5.12-5.28 (m, 2), 6.84 (d, 4, J=9), 6.87-6.95 (m, 1), 7.11-7.25 (m, 2), 7.29-7.38 (m, 5); MS: m/z=326(M+1). This material was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[N+:31]([O-])=O)[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].O.[Sn](Cl)Cl>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([NH:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[NH2:31])[CH2:20][CH:19]2[OH:34])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccc(F)cc3[N+](=O)[O-])CC2O)CCCCC1)c1ccco1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(O)C1
Temperature: 80 °C
Yield: 78.1 %

Procedure:
To the solution of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-nitrophenyl)piperidin-3-ol (7.0 g, 14.7 mmol) obtained in Step 1 in 70 ml of ethanol, was added tin (II) chloride hydrate (1.13 mg, 44.2 mmol). The reaction mixture was refluxed for about 4 hours at 80° C., and then cooled to room temperature and concentrated. The resulting residue was diluted with 100 ml of ethyl acetate, alkalized with 29% aqueous ammonia solution (pH 8), and then the resulting white solid was filtered out. 100 ml of distilled water was added to the resulting filtrate. The resulting organic layer was dried and concentrated on sodium sulfate to give the titled compound (5.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl-].[NH4+].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:14][N:13]=[N:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 102.2 %

Procedure:
3-Bromo-benzonitrile 8a (18.2 g, 0.1 mol) and ammonium chloride (5.9 g, 0.11 mol) were dissolved in 80 mL of N,N′-dimethylformamide followed by addition of sodium azide (7.16 g, 0.11 mol) under argon atmosphere. The reaction mixture was heated to 100° C. and reacted overnight. Then the mixture was cooled to 60° C. and concentrated under reduced pressure to remove N,N′-dimethylformamide. The residue was diluted with 100 mL of water and 4 mL of concentrated hydrochloric acid and stirred for 1 hour. The mixture was filtered and dried to obtain the title compound 5-(3-bromo-phenyl)-1H-tetrazole 8b (23 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Cl.[CH3:14][NH2:15]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][NH:15][CH3:14]
Reactant: CN
Reactant: Cc1cccc(C)c1NC(=O)CCl
Product: CNCC(=O)Nc1c(C)cccc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A closed stainless-steel reactor is charged with 80 g of N-(2,6-dimethylphenyl)-2-chloro-acetamide and 600 ml of a 40% aqueous methylamine solution. The mixture is heated with stirring at 80° C. for 4 h and then concentrated under vacuum. The crude product is taken up in water and washed with dichloromethane. The aqueous solution is basified using sodium hydroxide solution and extracted with dichloromethane. The organic, phase is dried over sodium sulphate and concentrated to give 60 g of a colourless oil.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[N+:16]([O-])([OH:18])=[O:17]>C(OC)(C)(C)C>[Cl:6][C:7]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: COC(C)(C)C
Product: O=Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 42 °C
Reaction time: 1.83 h
Yield: 28.7 %

Procedure:
Concentrated sulphuric acid (450 Kg) was added to 2,3-dichlorobenzaldehyde (59 Kg) and the mixture was heated to 40-44° C. for 2 hours, with stirring, to dissolve all the solids then cooled to 20-25° C. over a period of 95 minutes. Nitric acid (70% w/w, 34.5 Kg) was added to the solution, maintaining the temperature between 16 and 28° C., over a period of 110 minutes. The reaction mixture was stirred for 130 minutes, at between 21-25° C., and then quenched by controlled addition over 225 minutes into 1080 Kg of water (pre-cooled to 0-5° C.), maintaining the temperature between 2-20° C., including a vessel rinse of concentrated sulphuric acid (9.2 Kg). The resulting suspension was stirred for 180 minutes at between 10-14° C. then isolated by filtration and washed with pre-cooled (0-15° C.) water (2×297 Kg). The isolated crude solid (151.3 Kg crude, 51.6 kg active weight) was dissolved in methyl tert-butyl ether (590 L) and washed with water (165 L), 10% w/w sodium carbonate solution (165 L) and then water (1654 Solvent was removed by reduced pressure distillation at 17-20° C. until a volume of 160 L was reached, whereupon heptane (1140 L) was added. The resulting slurry was heated to 60° C. over 54 minutes and stirred at between 60-65° C. for 110 minutes, then cooled to 15-20° C. over 11.5 hours. Material was isolated by filtration and washed with heptane 90 L) then dried in vacuo at 40-45° C. to give 2,3-dichloro-6-nitrobenzaldehyde (21.3 Kg) with 96.3% purity (HPLC) in 29% yield.
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[OH2:4].[OH2:5].O.O.[N+]([O-])([O-])=O.[Ca+2:12].[N+]([O-])([O-])=O>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[Ca+2:12]
Reactant: O
Reactant: O=[PH2]O
Agent: *CC*
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
An aqueous solution of 8.51 g 50 wt % hypophosphorous acid, H3PO2 (Alfa/Aesar reagent #14142, CAS #6303-21-5), equivalent to 71.95 wt % [PO4]−3 was combined with 8.00 g distilled water to form a clear, colorless solution contained in a 250 ml Pyrex beaker. To this solution was added 22.85 g calcium nitrate tetrahydrate salt, Ca(NO3)2.4H2O (ACS reagent, Aldrich Chemical Co., Inc. #23,712-4, CAS #13477-34-4), equivalent to 16.97 wt % Ca. The molar ratio of Ca/phosphate in this mixture was 3/2 and the equivalent solids level [as Ca3(PO4)2] was 25.4 wt %. Endothermic dissolution of the calcium nitrate tetrahydrate proceeded under ambient temperature conditions, eventually forming a homogeneous solution. Warming of this solution above 25° C. initiated a reaction in which the solution vigorously bubbled while evolving red-brown acrid fumes characteristic of NOx(g). The sample turned into a white, pasty mass which foamed and pulsed with periodic expulsion of NOx(g). After approximately two minutes, the reaction was essentially complete, leaving a white, pasty mass which was warm to the touch. After cooling to room temperature, the solid (A) was stored in a polyethylene vial.
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]([CH3:22])[O:19][CH2:20][CH:21]=3)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>>[CH3:22][CH:18]1[CH:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:21][CH2:20][O:19]1
Reactant: CC1OCC=C1c1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: [H][H]
Product: CC1OCCC1c1ccc2c(c1)CNC2

Procedure:
Prepared in analogy to Example A62(c) from 2-benzyl-5-(2-methyl-2,5-dihydro-furan-3-yl)-2,3-dihydro-1H-isoindole and hydrogen. Yellow oil. MS (m/e): 204.1 ([M+H]+, 100%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][OH:6].Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1.[Cl-].[Na+]>CN(C)C=O>[F:3][C:4]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:5][O:6][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1
Reactant: OCC(F)(F)C(F)(F)F
Reactant: N#Cc1cc(Cl)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)C(F)(F)F)ccn1
Reaction time: 0.42 h
Yield: 75.6 %

Procedure:
Into 6 ml of N,N-dimethylformamide was suspended 0.16 g of sodium hydride (60% oily), and 0.52 g of 2,2,3,3,3-pentafluoro-1-propanol was added at 10° C. After stirring for 25 minutes, 0.4 g of 4-chloropyridine-2-carbonitrile was added, the mixture was stirred for 3 hours, and the reaction solution was poured into an aqueous saturated sodium chloride solution, followed by extraction with tert-butyl=methyl=ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.55 g of 4-(2,2,3,3,3-pentafluoropropoxy)pyridine-2-carbonitrile.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(OC(=O)C)(C)C>C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(I)c(N)n1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)OC(C)C
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccccc2OC(F)(F)F)c(N)n1
Temperature: 78 °C

Procedure:
To a suspension of 3-iodopyridine-2,6-diamine (5 g, 21 mmol), 2-(trifluoromethoxy)phenyl boronic acid (4.82 g, 23 mmol) and sodium carbonate (2.48 g, 23 mmol) in ethanol (25 ml) and water (25 ml) was added tris(dibenzylideneacetone)dipalladium (0.292 g, 0.319 mmol) followed by tri-tert-butylphosphine (1M solution in toluene, 0.957 ml, 0.957 mmol). The reaction was heated to 78° C. for 16 hours before cooling to room temperature and addition of isopropylacetate (50 ml). The bi-phasic mixture was filtered through Arbocel™ and the filter cake washed with isopropylacetate (2×25 ml). The layers were separated and the organic phase washed with half saturated aqueous sodium hydrogen carbonate solution (50 ml) and water (2×25 ml) before concentration in vacuo. Toluene (2×25 ml) was added during the concentration process and evaporation continued to dryness. The crude residue was purified using silica gel column chromatography (Biotage™) eluting with isopropanol:toluene 5:95 to furnish the title compound as a solid, 90%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([F:12])([CH2:8][CH:9]([F:11])[F:10])[C:4](Cl)([F:6])[F:5].[F:15]C(F)=C>>[F:1][C:2]([F:14])([F:13])[C:3]([F:12])([CH2:8][CH:9]([F:11])[F:10])[C:4]([F:15])([F:6])[F:5]
Reactant: C=C(F)F
Reactant: FC(F)CC(F)(C(F)(F)F)C(F)(F)Cl
Product: FC(F)CC(F)(C(F)(F)F)C(F)(F)F

Procedure:
As another example, 2-trifluoromethyl-1-chloro-1,1,2,4,4-pentafluorobutane may be prepared by reacting commercially available 1,1-difluoroethylene according to the procedure of George L. Fleming et al., supra, to form a product which may then be hydrogenated to form 2-trifluoromethyl-1,1,1,2,4,4-hexafluorobutane which may then be chlorinated to form 2-trifluoromethyl-1-chloro-1,1,2,4,4-pentafluorobutane.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:34]=[CH:33][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1.O1CCCC1.[OH-].[Li+]>CO>[F:35][C:2]([F:1])([F:36])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:33][CH:34]=3)[CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(Nc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.7 %

Procedure:
Isomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and tetrahydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, 8.4 mmol). The mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acidified to pH=4 with 1.0M aqueous hydrochloric acid. A brown precipitate formed. The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenylamino)butyl)benzamido)propanoic acid, Isomer 1 (0.220 g, 78%) as a solid. 1H NMR (400 MHz, CDCl3, δ): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J=7.6 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H), 7.27 (d, J=7.2 Hz, 2H), 7.03-6.88 (m, 1H), 6.60-6.42 (m, 2H), 4.33 (t, J=6.3 Hz, 1H), 3.64 (s, 2H), 2.72-2.54 (m, 2H), 1.87-1.65 (m, 2H), 1.51-1.22 (m, 2H), 0.90 (t, J=7.0 Hz, 3H). MS (M+1): 475.2.
Reaction SMILES: [CH2:1]([C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])([CH2:8]CCC)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].C(Br)[Br:21].[OH-].[Na+]>CS(C)=O>[Br:21][CH2:8][C:5]([C:6]#[N:7])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C#N)(CCCC)c1ccccc1OC
Reactant: BrCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCC(C#N)(CBr)c1ccccc1OC
Yield: 65.6 %

Procedure:
A 5 liter three neck round bottom flask equipped with mechanical stirrer was charged with 500 grams (2.46 moles, 1.0 ec.) of alpha-n-butyl-alpha-(2-methoxyphenyl) hexanenitrile and 2500 ml of DMSO and 513 grams of CH2Br2 (2.95 moles, 1.20 ec.). To the reaction was added dropwise over 3 hours 394 grams (4.92 moles, 2.0 eq.) of 50% NaOH. Upon addition of the base the reaction exothermed to 55° C. and was maintained at that temperature during the addition and for two hours following the completion of the addition. The reaction was 90% complete and was quenched by the addition of water. The product was isolated with ether and washed with water and brine. Distillation of the crude material gave 478 grams of product (66% yield, 90% pure) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]2[CH2:14][CH2:15][C@@H:9]1[CH2:10][CH:11]([C:16]([OH:18])=[O:17])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[C@@H:13]12[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([CH2:15][CH2:14]1)[CH2:10][CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]2
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(C(=O)O)C2
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)C1C[C@H]2CC[C@@H](C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
To a solution of (1R,5S)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (500 mg, 1.96 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (541 mg, 3.92 mmol) and methyl iodide (0.18 mL, 2.94 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with ethyl acetate (50 mL) and heptanes (50 mL), and then washed with water (100 mL) and brine (50 mL). The organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave the title compound (486 mg, 92%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 4.17-4.29 (m, 2H), 3.65 (s, 3H), 2.75-2.86 (m, 1H), 1.93-2.01 (m, 2H), 1.79-1.92 (m, 2H), 1.67-1.76 (m, 2H), 1.58-1.66 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:31][CH2:30][S:29][CH2:28][CH2:27]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:21]4=[C:22]([CH2:25][N:26]5[CH2:27][CH2:28][S:29](=[O:43])[CH2:30][CH2:31]5)[CH:23]=[CH:24][N:20]4[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: Fc1cccc(Cn2ncc3cc(Nc4ncnn5ccc(CN6CCSCC6)c45)ccc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S1CCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)CC1
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A solution of [1-(3-fluoro-benzyl)-1H-indazol-5-yl]-[5-(thiomorpholin-4-ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl]-amine (46 mg, 0.096 mmole) in chloroform (2 mL) was cooled in an ice bath and m-chloroperbenzoic acid (26 mg, 65%, 1 equiv) was added in portions over 12 min. After 1 hr, the reaction was then diluted with chloroform, washed with 6% aq. NaHSO3 solution, sat. aq. NaHCO3 solution and dried (Na2SO4). The solvent was removed and purification by radial chromatography (2 mm silica gel plate employing gradient elution with DCM containing 0 to 5% MeOH) afforded the title compound as an oil (13 mg, 27%). MS: 490 (M+H)+; HPLC Ret Time: 1.62 min (YMC S5 C18, 4.60×50 mm column, 3 min gradient, 4 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:21]([NH2:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24].C1C(Cl)=CC=C(Cl)C=1>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:21]([NH:22][S:33]([C:29]3[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:32]=[CH:31][CH:30]=3)(=[O:35])=[O:34])=[N:20][C:19]3[C:14]([N:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Reactant: CC(=O)Nc1cccc(S(=O)(=O)Cl)c1
Solvent: Clc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccc(NC(C)=O)c2)cc(OC)c1
Temperature: 25 °C
Yield: 24 %

Procedure:
N-(3,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.168 mmol), 3-Acetylaminobenzene sulfonylchloride (59 mg, 0.5 mmol, commercially available from INTERCHIM) are dissolved in a 1 to 2 mixture of pyridine: dichlorobenzene (0.3 ml) and the reaction mixture is heated to 150° C. overnight in an orbital shaker. When TLC confirms the total consumption of the starting material, the reaction mixture is cooled down to rt. The precipitate formed is filtered and purified by column chromatography, using Pet.Ether: EtOAc as eluent, to afford 20 mg (24%) of the title compound as a yellow solid. HPLC (max plot) 89%, rt. 4.08 min. LC/MS: (ES+): 494.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[C:17]([CH:22]([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[C:17]([CH:22]([F:24])[F:23])=[N:18][N:19]([CH3:21])[CH:20]=2)=[S:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cc(C(=O)Nc2ccccc2C2CCCCC2)c(C(F)F)n1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=S)Nc2ccccc2C2CCCCC2)c(C(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-(2-cyclohexylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (2.0 g) and Lawesson's reagent (2.4 g) were refluxed in toluene (100 mL) for 1 h. Contents were stirred overnight at RT and filtered. The filtrate was concentrated in vacuo leaving a yellow solid which was chromatographed on silica gel eluting with 35% EtOAc/hexanes to give a yellow solid. The solid was recrystallized from EtOAc to give the desired compound as a yellow solid (1.1 g).
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=3)[N:9]=[C:10]([CH3:12])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([CH:19]([C:22]1[C:23]2[N:24]([C:29](I)=[C:30]([CH3:32])[N:31]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:20][CH3:21])[CH3:18]>>[CH:1]1([C:6]2[C:7]3[N:8]([C:13]([C:29]4[N:24]5[N:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH:19]([CH2:17][CH3:18])[CH2:20][CH3:21])[C:23]5=[N:31][C:30]=4[CH3:32])=[C:14]([CH3:16])[N:15]=3)[N:9]=[C:10]([CH3:12])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cn2nc(C)cc(C3CCCC3)c2n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C5CCCC5)cc(C)nn34)c(C)nc12
Yield: 53.8 %

Procedure:
Using a procedure analogous to Example 16B, 8-cyclopentyl-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.41, 1.86 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.63 g, 1.86 mmol) give the title compound (0.43 g, 1.0 mmol, 54%). 1H NMR (CDCl3): δ 0.92 (t, J=7.4 Hz, 6H), 1.70-1.96 (m, 10H), 2.25-2.35 (m, 2H), 2.43 (s, 3H), 2.44 (s, 3H), 2.47 (s, 6H), 3.35-3.48 (m, 1H), 3.78-3.90 (m, 1H), 6.68 (s, 1H), 6.76 (s, 1H) ppm. ES-MS (m/z): calcd for C26H34N6 (M+H)+: 431.6. found: 431.3.