Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>O>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[C@H:13]([CH3:17])[CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2nc3cc(C(F)(F)F)cc(Cl)c3[nH]2)CCN1c1ncccc1C(F)(F)F
Temperature: 250 °C

Procedure:
A mixture of the piperazine from step (a) above (80 mg, 0.25 mmol), 2-chloro-3-trifluoromethyl-pyridine (54 mg, 0.3 mmol, Aldrich) and NAN-diisopropylethylamine (0.5 mL, 2.9 mmol, Aldrich) was heated in a microwave synthesizer for 120 min at 250° C. Water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 35% EtOAc/hexane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27](O)=[O:28])=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][C:14]([F:34])=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=CC(OC3C(C(NCC4C=CC(O[C@H](C)C(O)=O)=CC=4F)=O)=CC=C[N:46]=3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][C:14]([F:34])=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:28])[NH2:46])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Product: C[C@@H](Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O

Procedure:
The compound of Formula (5.5.18) was prepared in a manner analogous to that described in Example 14, substituting (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid for the corresponding (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid material.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:32])=[C:24]([CH2:27][CH2:28][C:29]([OH:31])=O)[CH:25]=2)[NH:20][C:19](=[O:33])[C:18]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:45][CH2:46][CH2:47][N:48]=[C:49]=NCC.ON1C2C=CC=CC=2N=N1.N1CCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:32])=[C:24]([CH2:27][CH2:28][C:29](=[O:31])[N:48]3[CH2:49][CH2:45][CH2:46][CH2:47]3)[CH:25]=2)[NH:20][C:19](=[O:33])[C:18]=1[C:34]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[CH:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCNC1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Reaction time: 0.17 h
Yield: 55 %

Procedure:
To a solution of 2-{2-[6-(2-carboxyethyl)-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (15 mg in 0.5 mL of dry methylene chloride) was added 8.0 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) followed by 5.2 mg 1-hydroxybenzotriazole (HOBt) and the mixture stirred for 10 minutes. At this time, 9.2 mg of pyrrolidine was added and the reaction allowed to proceed at room temperature. After 40 minutes, the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride: 10% ammonium hydroxide in methanol, 95:5; then 90:10) to give the title compound (9 mg).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[OH:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)c1cc(O)ccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccccc2)c(C(=O)OCC)c1
Yield: 85.9 %

Procedure:
The above-prepared 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate, 4.62 g (19.1 mM) of ethyl p-hydroxybiphenylcarboxylate and 6 ml of dimethylformamide (DMF) were mixed and sufficiently stirred. To the mixture, 0.77 g (19.3 mM) of 60% -sodium hydride was added, followed by heat-refluxing for 7 hours. After the reaction, the reaction mixture was subjected to distilling-off of DMF and addition of water, followed by extraction with ether to obtain an extract. The extract was dried with anhydrous sodium sulfate, followed by distilling-off of ether and purification by column chromatography (eluent: methylene chloride) to obtain 6.46 g (16.4 mM) of ethyl p-(10-undecenyl)oxybiphenylcarboxylate (Yield: 86%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)=[O:4].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:6]=1)[OH:4]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
Under nitrogen atmosphere, a solution of 2-bromo-1-[4-(phenyl-methoxy)-3-[(methylsulfonyl)amino]phenyl]ethanone (J. Med. Chem., vol. 23, no. 7, p. 738 (1980)) (977 mg, 2.45 mmol) and (R)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (170 mg, 0.61 mmol) in tetrahydrofuran is stirred for 30 minutes. The mixture is cooled to −30° C., and thereto is added a 2M borane-dimethylsulfide complex in tetrahydrofuran (1.84 mL, 3.68 mmol), and the mixture is stirred at −25° C. for 2 days. The reaction solution is warmed to room temperature, and ethyl acetate and a saturated aqueous ammonium chloride solution are added thereto, and the mixture is stirred. The organic layer is collected and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate/chloroform=1/50) to give the desired (R)-2-bromo-1-[4-(phenylmethoxy)-3-[(methylsulfonyl)-amino]phenyl]ethanol (881 mg, yield: 90%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:5](I)[CH:4]=1)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[N:31][CH:32]=1)#[CH:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[C:12]([O:11][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[C:26]#[C:25][C:27]1[CH:28]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH:30]=[N:31][CH:32]=1)=[O:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1I
Reactant: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cc(C#N)ccc2NC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Into a reaction flask were added tert-butyl (4-cyano-2-iodophenyl)carbamate (1.4 g, 4.1 mmol), copper(I) iodide (31 mg, 0.16 mmol), bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.16 mmol), tetrahydrofuran (10 mL), and triethylamine (0.63 mL, 4.5 mmol). The mixture was stirred under N2 bubbling for 5 minutes and tert-butyl (5-ethynylpyridin-3-yl)carbamate (0.90 g, 4.1 mmol) (prepared according to Example 17, Step B) was then added. The reaction mixture was stirred at 65° C. for 2 hours. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product (0.94 g, 52%). LCMS for C24H27N4O4 (M+H)+: m/z=435.2.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:29])[C@H:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:14]C(OC(C)(C)C)=O)=[CH:7][CH:6]=1)([O-:4])=[O:3].CCOCC>O1CCCC1>[ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12](=[O:29])[C@H:13]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 22 °C
Reaction time: 1 h

Procedure:
250 ml of 5 N ethereal hydrogen chloride were added to a solution of 21 g of tert.-butoxycarbonyl-L-phenylalanine p-nitrophenyl ester in 50 ml of anhydrous tetrahydrofurane and the reaction mixture was stirred for 1 hour at 22° C., with exclusion of moisture. 250 ml of absolute ether were added to the precipitate formed and the yellowish crystals were isolated by filtration; 15.9 g (99% of theory) of melting point 191°-193° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=3)[C:8]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1(=O)CCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: Nc1ccc(CCO)cc1
Product: O=S1(=O)CCc2nc(-c3cccc(Cl)c3)nc(Nc3ccc(CCO)cc3)c21
Yield: 65.6 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.095 g, 0.22 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.036 g, 0.26 mmol) to afford the title compound (0.060 g, 65%) as a white solid. MW=415.89. 1H NMR (DMSO-d6, 500 MHz) δ 9.51 (s, 1H), 8.24-8.17 (m, 2H), 7.64-7.60 (m, 1H), 7.58-7.53 (m, 3H), 7.27 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.72 (t, J=7.0 Hz, 2H), 3.67-3.62 (m, 2H), 3.44-3.38 (m, 2H), 2.76 (t, J=7.0 Hz, 2H); APCI MS m/z 416 [M+H]+.
Reaction SMILES: [P:1]([O-:18])([O:10]CC1C=CC=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22]>C(#N)C.O>[CH2:3]([O:2][P:1]([O-:18])[O-:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22].[CH3:20][N+:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: [O-]P([O-])OCc1ccccc1

Procedure:
Dibenzyl phosphite (29.4 g, 112 mmol) is dissolved in a mixture of acetonitrile (140 mL) and water (30 mL) and the reaction mixture is treated with 2.8M aqueous tetramethylammonium hydroxide (40 mL, 112 mmol) at room temperature for 24 hours. After being washed with ether (3×20 mL), the aqueous layer is concentrated in vacuo. The residue is dried under high vacuum at 70° for 12 hours to yield tetramethylammonium benzyl phosphite as a semi-solid. The latter compound (2 g, 8 mmol) and α-(phenylacetoxy)isobutyl bromide (prepared from phenylacetyl bromide and isobutyraldehyde according to Helv. Chim. Acta 61, 2047, 1978) (1.26 mL, 8 mmol) are stirred in acetone (15 mL) for 18 hours at room temperature. The precipitate is filtered through Celite. The filtrate is concentrated under reduced pressure and purified by flash-chromatography on silica gel eluting with 37.5% of ethyl acetate in hexane. Evaporation of the pure fractions gives the unsymmetrical (α-phenylacetyloxyisobutyl) benzyl phosphite as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccccn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 23.5 %

Procedure:
A mixture of 2-hydroxypyridine (6.0 g), N-(4-bromobutyl)phthalimide (17.8 g), potassium carbonate (8.7 g) and N,N-dimethylformamide (DMF) (80 ml) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off under reduced pressure. The oily residue was subjected to a silica gel column chromatography. From the fraction eluted with chloroform-ethyl acetate (4:1 v/v), N-[4-(2-pyridyloxy)butyl]phthalimide (4.4 g, 23%) was obtained Recrystallization of the product from ether gave colorless prisms, m.p. 77° C. to 78° C.
Reaction SMILES: [CH2:1]([PH2:4])[CH2:2][CH3:3].[CH:5]([CH:7]=[O:8])=[O:6]>O1CCCC1>[CH2:1]([P:4]1[CH:5]([OH:6])[CH:7]([OH:8])[P:4]([CH2:1][CH2:2][CH3:3])[CH:5]([OH:6])[CH:7]1[OH:8])[CH2:2][CH3:3]
Reactant: O=CC=O
Reactant: CCCP
Solvent: C1CCOC1
Product: CCCP1C(O)C(O)P(CCC)C(O)C1O

Procedure:
Following the procedure of Example 1, mono-n-propylphosphine, in tetrahydrofuran, as solvent, is reacted with a 40% aqueous glyoxal solution, to give 1,4-di-n-propyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, a solid melting at 131°-133° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>>[C:13]([NH:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCCc2c(O)cccc21
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCc2c(O)cccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
50 mmol of 5-amino-1-hydroxy-5,6,7,8-tetrahydronaphthalene are stirred in a solution of 200 mmol of acetic anhydride and 200 mmol of triethylamine, to which a spatula-tip of dimethylaminopyridine has been added, for 2 hours. The mixture is filtered, the residue is rinsed thoroughly with tetrahydrofuran and the filtrate is evaporated. The residue is taken up in ethyl acetate and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl, saturated NaHCO3 and saturated NaCl solution, dried over Na2SO4 and evaporated. The bis-acetate which remains is dissolved in 100 ml of MeOH and the solution is then added dropwise to 100 ml of 1N KOH at room temperature. The mixture is stirred at an internal temperature of 50° C. for 2 hours and acidified with concentrated HCl and the MeOH is stripped off. The acid aqueous phase is extracted by shaking 2 to 3 times with ethyl acetate and the combined organic phases are dried with Na2SO4 and evaporated. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH2:33]1[O:35][C@H:34]1[CH2:36][OH:37]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:33][C@H:34]([OH:35])[CH2:36][OH:37])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OC[C@H]1CO1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C[C@H](O)CO)CC4)cn3)nc2n1C1CCCC1
Yield: 51.3 %

Procedure:
Following General Procedure E, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and (S)-(+)glycidol (51 mg, 0.691 mmol) gave 7-cyclopentyl-2-{5-[4-((S)-2,3-dihydroxy-propyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (60 mg, 50%). MS (ESI) m/z 509.3 (M+H)+
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(CCC2CCCO2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(CCC2CCCO2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
To an acetic acid (10 mL) solution of 4-(2-(tetrahydrofuran-2-yl)-ethyl)-benzaldehyde (565 mg, 2.77 mmol) described in Manufacturing Example 82-1-3 were added nitromethane (1.69 g, 27.7 mmol) and ammonium acetate (427 mg, 5.54 mmol) under nitrogen atmosphere at room temperature, which was stirred for 4 hours at 120° C. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (646 mg, 94%) as a crude product.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7]1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:8]3[CH2:9][CH:6]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:7]3)[S:11][C:12]=2[CH:18]=1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OC1CN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2nc(N3CC(N4CCCCC4)C3)sc2c1
Temperature: 92.5 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(6-bromobenzo[d]thiazol-2-yl)azetidin-3-yl methanesulfonate (Reference Example 12b, 61.7 mg, 0.17 mmol), piperidine (0.250 mL, 2.5 mmol), and potassium carbonate (0.062 g, 0.44 mmol) in N,N-dimethylformamide (1 mL) was stirred at 90-95° C. for two days. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with dichloromethane (2×4 mL). The combined organic extracts were washed with water (2×5 mL), then dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (90:10:0 to 88:10:2 dichloromethane/ethyl acetate/methanol). A second column was run with the same eluent gradient. Fractions containing product were combined and concentrated under reduced pressure to give 6-bromo-2-(3-(piperidin-1-yl)azetidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.58 (m, 2H), 1.64 (pentet, J=5 Hz, 1H), 2.35-2.45 (m, 4H), 3.36-3.46 (m, 1H), 4.02-4.08 (m, 2H), 4.24 (t, J=8 Hz, 2H), 7.35 (d, J=8 Hz, 1H), 7.42 (dd, J=2, 8 Hz, 1H), 7.83 (d, J=2 Hz, 1H); MS (ESI) m/z 352 (M+H)+.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][CH2:4][N:3]=[CH:2]1.[N+:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:9])=[O:8].CS>[Cl-].[Zn+2].[Cl-].CCOCC.C(O)(C)C>[N+:7]([C:10](=[C:2]1[NH:3][CH2:4][CH2:5][CH2:6][S:1]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:9])=[O:8]
Reactant: C1=CSC=NC1
Reactant: CCOC(=O)C[N+](=O)[O-]
Agent: CS
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reaction time: 1.25 h

Procedure:
To a mixture of 235 g of 5,6-dihydro-2-methylthio)-4H-1,3-thiazine and 2 g of zinc chloride at approximately 115° in a nitrogen atmosphere, 263 g of ethyl nitroacetate was added dropwise over a 1.5 hour period. The mixture was held at 110°-120°. When evolution of methyl mercaptan ceased after 45 minutes further stirring of the heated mixture, 1 g of zinc chloride was added and the mixture was stirred at about 115° for 1.25 hours. An additional 1 g of zinc chloride then was added and stirring of the mixture at about 115° was continued for 1.5 hours. The mixture then was poured into a cooled solution of 2/1 ether/isopropyl alcohol mixture. The crystallized product was collected, washed with ether and dried under reduced pressure to leave a tan solid, m.p. 100°-102°, which on recrystallization from methanol gave ethyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (1A) as a pale yellow solid, m.p. 105°-106°.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH:9]([CH3:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:3]=1.[F:15][C:16](I)([F:21])[C:17]([F:20])([F:19])[F:18]>[Cu].CS(C)=O>[CH3:14][CH:9]([C:4]1[CH:3]=[C:2]([C:16]([F:21])([F:15])[C:17]([F:20])([F:19])[F:18])[CH:8]=[CH:7][C:5]=1[NH2:6])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CC(C)c1cc(I)ccc1N
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: CC(C)CC(C)c1cc(C(F)(F)C(F)(F)F)ccc1N
Temperature: 130 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
4-Iodo-2-(1,3-dimethylbutyl)aniline (1.35 g, 4.45 mmol), copper powder (0.85 g, 13.4 mmol) and pentafluoroethyl iodide (1.42 g, 5.77 mmol) were added to dimethyl sulfoxide (10 ml), and the resulting mixture was stirred at 130° C. for 4 hours. The mixture was filtered through Celite and the filtrate was diluted with ethyl acetate and washed 4 times with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 1.24 g of the desired compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
MsCl (15.8 mL. 204 mmol) was added to a solution of 2-(2-(benzyloxy)ethoxy)ethanol (46) (25 g, 127 mmol) and Et3N (36 mL, 255 mmol) in DCM (180 mL) at 0° C., the reaction mixture was allowed to warm up to RT and stirred for 16 h. The reaction mixture was diluted with DCM (50 mL) and washed with water (2×50 mL), 1M HCl (aq.) (2×50 mL), the organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate (47) (35 g, 100%) as an orange oil: m/z 275 (M+H)+ (ES+). 1H NMR (400 MHz, CDCl3) δ: 7.37-7.27 (m, 5H), 4.55 (s, 2H), 4.40-4.37 (m, 2H), 3.78-3.76 (m, 2H), 3.71-3.68 (m, 2H), 3.64-3.62 (m, 2H), 3.02 (s, 3H).