Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][N:25]([CH3:34])[C:26]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[O:27])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:34][N:25]([CH2:24][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)[C:26]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: CN(Cc1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1)C(=O)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1cncc(-c2cnc3c(c2)CCCN3)c1)C(=O)C1CCOCC1
Reaction time: 16 h
Yield: 91 %

Procedure:
6-(5-{[Methyl-(tetrahydro-pyran-4-carbonyl)-amino]-methyl}-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (70 mg, 0.15 mmol) is dissolved in DCM (2.0 mL) and trifluoroacetic acid (0.5 mL) is added. The mixture is stirred for 16 hrs and the solvent is removed in vacuo. The residue is dissolved in MeOH and filtered through StratoSphere PL-HCO3 MP SPE cartridge, concentrated and dried to give 50 mg of crude tetrahydro-pyran-4-carboxylic acid methyl-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-ylmethyl]-amide which is used without purification.
Reaction SMILES: [C:1]([C@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[C@:7]([CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])([CH3:12])[N:6]1C(OC(C)(C)C)=O)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].O>C(Cl)Cl>[C:1]([CH:5]1[N:9]([CH3:10])[C:8](=[O:11])[C:7]([CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])([CH3:12])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1C(=O)[C@@](C)(CCCCCl)N(C(=O)OC(C)(C)C)[C@H]1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)C(C)(CCCCCl)NC1C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
To an ice cooled of (2S,5R)-tert-butyl 2-(tert-butyl)-5-(4-chlorobutyl)-3,5-dimethyl-4-oxoimidazolidine-1-carboxylate (D44) (465 mg, 1.28 mmol) in dry DCM (2 ml), TFA (1 ml, 12.8 mmol) was added and the solution stirred for 12 hrs at RT. The reaction mixture was treated with NaHCO3 sat sol with vigorous stirring until pH˜7. The resulting mixture was poured into water and the aqueous phase extracted with DCM (3×10 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D45) (310 mg).
Reaction SMILES: CC(O)C.[ClH:5].[C:6]([C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[O:20][N:19]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].[BH4-].[Na+]>CO>[ClH:5].[F:27][C:25]1[CH:24]=[CH:23][C:22]2[C:18]([CH2:17][CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][C:9]([CH:6]([OH:8])[CH3:7])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:14][CH2:13]3)=[N:19][O:20][C:21]=2[CH:26]=1
Reactant: CC(=O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: CC(O)C1(c2ccccc2)CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
To a mixture of 50 ml of 2-propanol and 10 ml of methanol, was added 2.8 g of 4-acetyl-1-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-4-phenylpiperidine hydrochloride and 0.76 g of sodium borohydride. After stirring at ambient temperature for twenty hrs, the mixture was evaporated. The residue was stirred with 100 ml of water for ten mins and then extracted with ether. The ether extract was washed with water (2×), saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, the ether solution was acidified to pH 1 with ethereal hydrogen chloride. The resultant precipitate was collected and dried to give 2.3 g (78%) of product, mp 80° C. Recrystallization from ethyl acetate/methanol (9:1) gave the analytical sample, mp 143°-147° C.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH:12]([CH2:13][CH3:14])[CH2:11]1.S(=O)(=O)(O)O>O>[CH2:2]([O:9][CH2:11][CH:12]([OH:10])[CH2:13][CH3:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCc1ccccc1
Reactant: CCC1CO1
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: CCC(O)COCc1ccccc1
Yield: 90 %

Procedure:
15.4 Grams (0.67 mole) of sodium are poured into a flask containing 3.500 g. (35.2 mole) of benzyl alcohol under nitrogen atmosphere. After the sodium is dissolved, the temperature is brought to 160°C, then 481 g. (6.7 mole) of 1,2-epoxybutane are added dropwise. The temperature is kept at 160°C during the approximately 2 hours addition period. The temperature is subsequently lowered to 120°C and the excess of the starting 1,2-epoxybutane is distilled off; then 33.8 g (0.335 mole) of concentrated sulfuric acid and 36 ml. of water are added to the reaction mixture and the resulting solid sodium sulfate is removed by filtration. The filtrate is distilled under reduced pressure, thus recovering pure 1-benzyloxy-2-butanol in a yield of 90%. B.p. 128-132/6 mmHg.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:24])=[O:4]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CNC(=O)c1sc(C(C)(C)C)cc1N
Solvent: Cc1ccccc1
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 18 h
Yield: 43 %

Procedure:
A solution of the N-methyl-3-amino-5-tert-butylthiophene-2-carboxamide (0.60 g, 2.83 mmol) and 4-methylphenyl isocyanate (0.36 mL, 2.83 mmol) in toluene (2 mL) was heated at the reflux temp. for 18 h. The resulting solution was concentrated under reduced pressure and the resulting solid was purified by flash chromatography (EtOAc/CH2Cl2) affording N-(2-methylcarbamoyl-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.42 g, 44%): mp 202-4° C.; 1H NMR (CDCl3) δ1.38 (s, 9H), 2.31 (s, 3H), 2.91 (d, J=4.9 Hz, 3H), 5.59 (bs, 1H), 7.11 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.90 (s, 1H), 10.53 (s, 1H).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:30][CH2:31][CH2:32][NH:6][CH:5]([CH3:9])[CH3:4])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3I)OCO4)[nH]c12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-Fluoro-8-(6-iodo-benzo[1,3]dioxol-5-ylmethyl)adenine (300 mg, 0.726 mmol), Cs2CO3 (285 mg, 0.87 mmol) and 1,3-dibromopropane (370 L, 3.63 mmol) in anhydrous DMF (5 mL) was stirred at 50° C. for 2 h. Following solvent removal, product (330 mg, 85%) was collected through silica gel column purification (CHCl3 then EtOAc:hexanes:CHCl3:i-PrOH at 4:2:4:0.4). MS m/z 534.0 (M+H)+. To this product, i-PrNH2 (10 mL) was added in excess and the resulting solution stirred at room temperature for 1 h. Excess amine was removed and product (230 mg, 75%) collected through silica gel column purification (CHCl3:EtOAc:i-PrOH:NH4OH at 4:4:2:0.3). 1H NMR (400 MHz, CDCl3) 7.29 (s, 1H), 6.59 (s, 1H), 5.94 (s, 2H), 5.89 (bs, 2H), 4.25 (s, 2H), 4.11 (t, J=7.0 Hz, 2H), 2.73-2.60 (m, 1H), 2.55 (t, J=6.8 Hz, 1H), 1.93-1.86 (m, 2H), 1.03-1.02 (d, J=6.0 Hz, 6H); 13C NMR (100 MHz, methanol-d4) 160.0, 158.4, 157.2, 152.4, 151.3, 149.4, 148.4, 133.1, 118.7, 110.6, 102.4, 88.5, 42.8, 40.1, 38.8, 27.6, 19.4; MS m/z 513.2 (M+H)+. HPLC: (a) 98.5% (60% water-40% acetonitrile); (b) 97.2% (20% to 50% acetonitrile).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]([O:12]C(C)(C)C)=O)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:17][C:18]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH2:28][C:29]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=2[F:38])=[CH:21][C:19]=1[NH2:20].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCCC1.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].C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]2[N:20]([C:19]3[CH:21]=[C:22]([O:27][CH2:28][C:29]4[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([F:37])[C:30]=4[F:38])[C:23]([O:25][CH3:26])=[CH:24][C:18]=3[Cl:17])[C:10](=[O:12])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3ncc(Br)nc32)cc1OCc1c(OC)ccc(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.6 %

Procedure:
A mixture of 3,5-dibromo-2-(tert-butoxycarbonylamino)pyrazine (0.26 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.25 g), tris(dibenzylideneacetone)-dipalladium(0) (34 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43 mg) and sodium tert-butoxide (0.1 g) in tetrahydrofuran (5 mL) was heated at reflux under an argon atmosphere for 1 hour. The reaction mixture was cooled to room temperature. To the reaction mixture was added ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added methylene chloride (5 mL) and trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (3 mL). To the solution were added 1,1′-carbonyldiimidazole (58 mg) and sodium hydride (55%, 32 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (84 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][OH:23].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.O.C(Cl)Cl>[CH3:30][S:31]([O:23][CH2:22][C@@H:7]1[C@H:8]([NH:11][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:21])[C:9](=[O:10])[N:6]1[CH2:5][C:4]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:3]=1[O:2][CH3:1])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2COS(C)(=O)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (5.37 g, 13.41 mmol) and TEA (3.72 mL, 26.8 mmol) in DCM at 0° C. was added MsCl (1.15 mL, 14.75 mmol). After stirring at 0° C. for 1 h, it was diluted with water/DCM and the layers were separated. The aqueous layer was extracted with DCM (2×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was taken up in toluene and concentrated (2×), affording the title compound as an off white solid. It was used as such in subsequent reactions. LCMS: Rt=0.86 min, m/z=479.2 (M+1) Method 2m_acidic.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: COc1cccc(CN)c1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1cccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 3-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.99 (M+H+); retention time=0.93 minutes.
Reaction SMILES: CS(O)(=O)=O.[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]1([CH3:17])[CH3:16].[C:18](#N)[CH3:19].OO>O.CS(O)(=O)=O.C1CCCCC1>[CH:19]1([O:6][N:7]2[C:12]([CH3:13])([CH3:14])[CH2:11][CH:10]([OH:15])[CH2:9][C:8]2([CH3:17])[CH3:16])[CH2:18][CH2:10][CH2:9][CH2:8][CH2:16]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CC#N
Agent: CS(=O)(=O)O
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Temperature: 62 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A solution of 0.234 g (0.842 mmol) of ferrous sulfate heptahydrate, 3 ml of water, and 0.293 g (3.05 mmol) of methanesulfonic acid is added to a mixture of 5.00 g (29.0 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-ol, 45 ml of acetonitrile, and 32 ml of cyclohexane, which has been heated to 62° C. A solution of 8.07 g (119 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2.25 hours to the reaction mixture while the temperature is maintained at reflux. A solution of 0.069 g of ferrous sulfate heptahydrate and 0.188 g of methanesulfonic acid in 2 ml of water is added to the reaction mixture 2 hours after the peroxide addition is started. A solution of 0.065 g of ferrous sulfate heptahydrate and 0.108 g of methanesulfonic acid in 1 ml of water is added to the reaction mixture 3.5 hours after the peroxide addition is started. After a total reaction time of 4.5 hours at reflux, the reaction mixture is allowed to cool. Excess peroxide is quenched with aqueous sodium sulfite solution. The aqueous layer is extracted with a 2:1 mixture of acetonitrile and cyclohexane, and the combined organic layers are washed with sodium hydroxide solution. To the organic layer are added 6 ml of t-butyl alcohol, 6 ml of water, 0.4 g of sodium hydroxide, and 0.70 g of sodium borohydride. The mixture is stirred for 3 hours, and the aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with aqueous citric acid, aqueous sodium bicarbonate, and then concentrated. Purification by flash chromatography with 1:1 heptane-ethyl acetate affords 5.10 g (69% yield) of the title compound as a light yellow syrup, GC assay 93%.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:23]=[CH:22][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]CC)[N:27]=1.C(N(CC)CC)C>C(#N)C>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:33]([NH:32][C:28]3[N:27]=[N:26][CH:31]=[CH:30][CH:29]=3)=[O:34])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)cc1
Reactant: CCOC(=O)Nc1cccnn1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cc3)c2)CC1
Temperature: 180 °C
Yield: 63.5 %

Procedure:
4-(3-(4-(Trifluoromethyl)phenoxy)benzylidene)piperidine hydrochloride (200 mg, 0.541 mmol, from Example 53, Step 5), ethyl pyridazin-3-ylcarbamate (99 mg, 0.595 mmol) and triethylamine (0.15 mL, 1.08 mmol) were combined in acetonitrile (4.5 mL) and heated in a microwave at 180° C. for 40 min. The reaction mixture was cooled to RT and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in CH2Cl2) to provide the title compound (156 mg). MS APCI M+ 455.2, 375.2, 334.2 M− 454.1; 1H NMR (400 MHz, CD3OD) δ ppm 2.46 (td, J=5.81, 0.84 Hz, 2H) 2.56 (td, J=5.81, 0.84 Hz, 2H) 3.55-3.61 (m, 2H) 3.65-3.70 (m, 2H) 6.44 (s, 1H) 6.91-6.99 (m, 2H) 7.06-7.14 (m, J=8.32 Hz, 3H) 7.35-7.43 (m, 1H) 7.59 (dd, J=9.13, 4.68 Hz, 1H) 7.61-7.66 (m, J=9.08 Hz, 2H) 8.12 (d, J=9.30 Hz, 1H) 8.78 (d, J=4.68 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](I)=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH:33]=[CH2:34].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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:34]=[CH:33]/[C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:17][C:16]=3[F:24])=[O:11])=[CH:4][CH:3]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(I)cc2c1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 100 °C

Procedure:
A mixture of the title compound of Example 5 (1.05 g), triethylamine (6 mL), ethyl acrylate (0.3 mL), palladium acetate (5.1 mg) and tris(o-tolyl)phosphine (42 mg) in DMF (5 mL) is heated to 100° C. for 24 h in a pressure-safe tube. The reaction is partitioned between CH2Cl2 and water. The aqueous layer is extracted with CH2Cl2 (3×). The combined organic layers are filtered, dried over Na2SO4, filtered and condensed. The crude product is purified by trituration with hot EtOAc to yield 0.461 g of the desired product as a tan solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1>CO.NN>[C:22]([O:21][C:20]([NH:19][C@@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][NH2:3])[CH2:18][CH2:17]1)=[O:26])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](ON)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A suspension of tert-butyl cis-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]-cyclohexylcarbamate (2.00 g) in MeOH (23 mL), hydrazine (26% in water, 1.1 mL) was added. After stirring at room temperature for 30 min, the mixture was filtered. The filtrate was evaporated to dryness and purified by flash chromatography (SiO2, CH2Cl2:MeOH 9:1) to give cis-4-(tert-butoxycarbonyl)aminocyclohexyloxyamine (0.80 g, 63%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 6.73 (1H, d), 5.75 (2H, bb), 3.45 (1H, m), 3.21 (1H, m), 1.30-1.90 (8H, m), 1.36 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)CCC.O.CCOC(C)=O>O1CCOCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 25.2 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (225 mg, 0.460 mmol) in dioxane (3 mL) was degassed with Ar before being charged with 4-tributylstannylpyridine (371 mg, 1.01 mmol) and Pd(Ph3P)4 (98 mg, 0.085 mmol). The mixture was stirred at 100° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (51 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.Cl>C1COCC1.O1CCOCC1>[NH2:8][C@@H:9]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=2)=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 119A (0.095 g, 0.14 mmol) in THF (1 mL) was treated with a solution of HCl in dioxane (0.25 mL, 4 N), stirred at 50° C. for 16 hours, cooled and concentrated under reduced pressure. The residue was dissolved in ethanol and concentrated several times to give the title compound as hydrochloride salt, which was used without further purification.
Reaction SMILES: [I-].[F:2][C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH3:24])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[ClH:25]>>[Cl-:25].[F:2][C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH3:24])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1
Reactant: Cl
Agent: Cc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Product: [Cl-]

Procedure:
A hot solution of 88 g. of 3-fluoro-10-methylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide in 6.4 l. of 6 N hydrochloric acid is cooled and the resulting precipitate of 3-fluoro-10-methylimidazo[1,2-a:3,4-a']diquinolin-15-ium chloride is collected by filtration, washed with 0.4 N hydrochloric acid, then with acetone, and dried; m.p. 345°-350° C. (dec.).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:26][C:27]([F:41])([F:40])[C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:37]3[CH2:38][CH2:39][N:34]([C:29]4[C:28]([C:27]([F:41])([F:26])[F:40])=[CH:33][CH:32]=[CH:31][N:30]=4)[CH2:35][CH2:36]3)=[O:16])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]2=[O:25])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Product: O=C(C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
1-Benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-[3-(trifluoromethyl)pyrid-2-yl]piperazine to give the title compound as a colorless solid. MS: 593.7 ([M+H]+)