Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](O)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[NH:71]1[CH2:74][CH:73]([OH:75])[CH2:72]1>CN(C)C=O.O>[F:1][C:2]1[C:3]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:71]4[CH2:74][CH:73]([OH:75])[CH2:72]4)=[O:19])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC1CNC1
Reactant: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)O)CC3)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3=CCN(CC(=O)N4CC(O)C4)CC3)cc12
Temperature: 70 °C

Procedure:
A mixture of Example 294A (0.100 g, 0.229 mmol), (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.143 g, 0.275 mmol), triethylamine (0.160 mL, 1.147 mmol), and azetidin-3-ol.hydrochloride (0.030 g, 0.275 mmol) in N,N-dimethylformamide (2.5 mL) was stirred for 3 hours and was treated slowly with water. The solid was filtered, washed with water, dried in a vacuum oven, heated in 6 mL ethyl acetate/heptanes (1:1) at 70° C. for 2 hours, filtered, washed with ethyl acetate/heptanes (1:1), and vacuum oven-dried to give the title compound. 1H NMR (500 MHz, Methanol-d4) δ 2.54-2.60 (m, 2H), 2.78 (t, J=5.7 Hz, 2H), 3.21 (d, J=2.9 Hz, 2H), 3.29 (d, J=3 Hz, 1H), 3.76 (s, 4H), 4.02-4.08 (m, 1H), 4.22 (dd, J=10.7, 6.8 Hz, 1H), 4.44-4.52 (m, 1H), 4.52-4.62 (m, 2H), 6.16 (s, 1H), 6.34-6.39 (m, 1H), 7.08-7.24 (m, 3H), 8.07 (d, J=2.8 Hz, 1H). MS (ESI+) m/z 455.0 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][C:27]=2[CH2:36][P:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCCC)CCCC)CCC.C([SiH](Cl)Cl)C>C1(C)C(C)=CC=CC=1>[C:45]1([P:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:26]=2[C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:24]=[CH:25][C:16]=2[CH2:15][P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=P(Cc1ccc2ccccc2c1-c1c(CP(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12)(c1ccccc1)c1ccccc1
Agent: CC[SiH](Cl)Cl
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: c1ccc(P(Cc2ccc3ccccc3c2-c2c(CP(c3ccccc3)c3ccccc3)ccc3ccccc23)c2ccccc2)cc1

Procedure:
20.48 g (0.03 mol) of 2,2'-bis(diphenylphosphinylmethyl)-1,1'-binaphthyl are suspended in 80 ml of xylene and 39.3 ml (0.165 mol) of tri-n-butylamine in the absence of air and moisture, and 19.4 g (0.15 mol) of ethyldichlorosilane are added dropwise with stirring. The mixture is then refluxed for 13 hours to give a clear solution. Xylene is distilled off at atmospheric pressure, and the mixture is allowed to cool with stirring. This results in the formation of 2,2'-bis(diphenylphosphinomethyl)-1,1'-binaphthyl as a colorless solid, which is filtered off under an inert gas and washed with 20 ml of degassed acetone. 18.5 g (95%) of colorless crystals of melting point 160° to 161° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:34][C:23]2=[CH:24][C:25]3[C:26](=[O:33])[N:27]([CH3:32])[C:28](=O)[C:29]=3[CH:30]=[C:22]2[N:21]=1)[CH3:11]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:21][C:22]2=[CH:30][C:29]3[CH2:28][N:27]([CH3:32])[C:26](=[O:33])[C:25]=3[CH:24]=[C:23]2[N:34]=1)[CH3:11]
Reactant: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C)C3=O
Yield: 62.7 %

Procedure:
2-(4-(1-(2,5-Difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.33 g, 0.71 mmol) and zinc powder (1.12 g, 17.09 mmol) were suspended in acetic acid (30 mL). The reaction mixture was stirred and heated to reflux overnight under argon. Then, the solvent was removed under reduced pressure. The residue solid was stirred in 100 mL of saturated K2CO3 solution. The white solid was filtered out, dried under vacuum and extracted with CH2Cl2/MeOH (7/3 v/v) three times (100 mL). The extracts were concentrated to dryness. The residue was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a pale-yellow solid product, 0.20 g, 62.7% yield. MS: 448.0 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.04 (s, 1H), 11.23 (s, 1H), 11.14-11.11 (m, 1H), 7.96 (s, 0.5H), 7.84 (s, 0.5H), 7.79 (s, 0.5H), 7.68 (s, 0.5H), 7.41-7.34 (m, 2H), 7.22-7.16 (m, 1H), 7.11-7.05 (m, 1H), 4.49 (s, 2H), 4.16-4.13 (m, 1H), 3.10 (s, 3H), 3.07-2.94 (m, 2H), 1.34-1.31 (m, 3H).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1>[Rh].O>[ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:3]1
Reactant: O=C(O)CCCc1ccncc1
Agent: [Rh]
Agent: Cl
Solvent: O
Product: O=C(O)CCCC1CCNCC1
Reaction time: 3 h
Yield: 98 %

Procedure:
The procedure of Example 1 was repeated except the following. The same reactor as used in Example 1 was charged with 25.0 g (0.124 mole) of a γ-(4-pyridyl)butyric acid hydrochloride with a purity of at least 99%, 25.0 g of water and 1.25 g of 5% Rh/C [0.25% by weight in terms of Rh based on the γ-(4-pyridyl)butyric acid hydrochloride]. The reaction was conducted for 3 hours. A γ-(4-piperidyl)butyric acid hydrochloride was produced in a yield of 98%.
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([CH3:20])[C:14]3[N:15]([CH:17]=[N:18][N:19]=3)[N:16]=2)[CH2:7][CH:6]1[Se:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:20][C:13]1[C:14]2[N:15]([CH:17]=[N:18][N:19]=2)[N:16]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([OH:4])[CH:6]([Se:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:7]2)[CH:12]=1
Reactant: CC(=O)OC1CCN(c2cc(C)c3nncn3n2)CC1[Se]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(O)C([Se]c3ccccc3)C2)nn2cnnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.6 g of 4-acetoxy-1-(8-methyl-1,2,4-triazolo [4,3-b]pyridazin-6-yl)-3-(phenylselenyl)piperidine in 25 ml of ethanol was stirred at room temperature while 10 ml of 1N sodium hydroxide was added. After stirring an additional 30 minutes at room temperature, the reaction was partitioned in water/dichloromethane. The layers were separated, the aqueous phase was washed with fresh dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate and evaporated to give a colorless glass. When this material was boiled in 50 ml of ethyl acetate, a crystalline material formed. After cooling to room temperature, the product was collected and dried to give 1-(8-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-3-(phenylselenyl)-4-piperidinol melting at about 157°-160° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([NH:6][C:7]2[C:12]([F:13])=[CH:11][N:10]=[C:9]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=4)[N:16]([S:24]([C:27]4[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH:15]=3)[N:8]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:43]([S:46](Cl)(=[O:48])=[O:47])[CH2:44][CH3:45].N1CCOCC1>C1COCC1>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([C:9]3[N:8]=[C:7]([NH:6][CH:4]4[CH2:3][N:2]([S:46]([CH2:43][CH2:44][CH3:45])(=[O:48])=[O:47])[CH2:5]4)[C:12]([F:13])=[CH:11][N:10]=3)=[CH:15][N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:17]2=[N:18][CH:19]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCN1
Product: CCCS(=O)(=O)N1CC(Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 50 °C
Yield: 43 %

Procedure:
To a stirred suspension of N-(azetidin-3-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine hydrochloride, 6c, (0.055 g, 0.110 mmol) in THF (1 mL) was added iPr2NEt (0.300 mL, 1.720 mmol) followed by propane-1-sulfonyl chloride (0.012 mL, 0.108 mmol). The resulting homogenous light yellow solution mixture was heated at 50° C. for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube for 10 minutes. The resulting solution was quenched with aqueous saturated NH4Cl solution (0.5 mL) then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 19.8 mg (43% yield) of the desired product, 423, as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH2:28]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[NH2-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]([CH2:18][CH:19]=[CH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:8]([CH:21]([CH3:22])[CH3:23])[N:7]=1)([CH3:26])[CH3:25]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1nc(C(C)C)c(CC=Cc2ccccc2)c(-c2ccc(F)cc2)c1CO

Procedure:
The title compound was prepared from the intermediate obtained in Step A and benzyl triphenylphosphonium bromide/sodium amide according to the procedures described in Example 1, Steps F-G. The product was obtained as a 6:4 mixture of trans:cis isomers. 1H NMR (300 MHz, CDCl3): δ 7.19 (m, 8 H), 6.96 (m, 1 H), 6.32 (d, J=11 Hz, 0.4 H), 6.09 (dt, J=5.5, 16 Hz, 0.6 H), 5.96 (d, J=16 Hz, 0.6 H), 5.45 (dt, J=7, 11 Hz, 0.4 H), 4.37 (d, J=5 Hz, 1.25 H), 4.33 (d, J=5.5 Hz, 0.75 H), 3.41 (m, 1.6 H), 3.25 (m, 2 H), 3.08 (m, 0.4 H), 1.35 (m, 5 H), 1.30 (d, J=6.6 Hz, 5 H), 1.21 (m, 3 H). FAB-MS: calcd for (C27H30FNO) 403, found 404 (M+H). Anal. Calcd for C27H30FNO: C, 80.36; H, 7.49; N, 3.47. Found: C, 80.15; H, 7.44; N, 3.26. mp 72-73° C. Rf=0.3 (20% ethyl acetate/hexane).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C@@H:13]2[CH2:16][CH2:15][N:14]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=O)[CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:39]=[N+:40]=[N-:41]>ClCCCl.ClCCl.CO>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C@H:13]1[C:11]1[N:10]([CH2:9][CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:41]=[N:40][N:39]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(NCCCc1cccnc1)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: [N-]=[N+]=N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CC[C@H]1c1nnnn1CCCc1cccnc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution of (2S)-N-[3-(3-Pyridyl)-1-propyl]-1-(benzyloxycarbonyl)azetidine-2-carboxamide from Reference Example 16 (295.7 mg, 0.837 mmol, 1.0 eq) in dry 1,2-dichloroethane (8.5 mL) was added pyridine (100 μL, 1.24 mmol, 1.5 eq) under argon. Phosphorus pentachloride (263 mg, 1.26 mmol, 1.5 eq) was added in one portion and the mixture was stirred at about room temperature for about 4 hours. A dry HN3 solution (prepared by mixing 6.5 g of NaN3 in 25 mL of water with 8.3 mL conc. HCl, extracting with 25 mL 1,2-dichloroethane, drying over magnesium sulfate and filtering) was added and the reaction mixture was stirred at about room temperature overnight. The organic phase was washed with concentrated NH4OH solution (2×5 mL), dried and the solvents removed under vacuum. Flash chromatography (5-10% methanol in dichloromethane) gave 125.3 mg (40% yield) of the product as a colorless oil. 1H NMR (CDCl3) δ 2.11-3.51 (series of m, 7H); 4.08-5.40 (series of m, 6H); 7.12-7.57 (m, 7H); 8.37-8.51 (m, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:3]=1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:3]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1cccnc1)OCc1ccccc1
Temperature: 130 °C
Reaction time: 20 h
Yield: 70 %

Procedure:
To a suspension of 3-(3-pyridyl)propionic acid hydrochloride (1.51 g, 10.0 mmol) in benzyl alcohol (3.1 mL, 30 mmol) was added p-toluenesulfonic acid monohydrate (181.8 mg, 0.96 mmol), and the mixture was stirred at 130° C. for 20 h. The reaction mixture was diluted with ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution was added to separate the phases. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated with reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate1:1→1:3) to give 1.69 g of the title compound as oil (yield: 70%).
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:13]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(OCC)(=O)C>C(O)C>[C:13]([C:15](=[CH:21][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1](=[O:11])(=[O:12])[CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: Nc1ccc2c(c1)CCS2(=O)=O
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C#N)=CNc1ccc2c(c1)CCS2(=O)=O
Yield: 82.1 %

Procedure:
5 g (27.3 mmol) of 2,3-dihydro-1-benzothiophen-5-amine 1,1-dioxide were suspended in 50 ml of ethanol under argon, 4.62 g (1 eq, 27.3 mmol) of ethyl 2-cyano-3-ethoxyacrylate were added, and the mixture was heated under reflux overnight. For working up, ethyl acetate was added to the mixture, and the precipitate which formed was filtered off with suction on a frit. The solid was dried in vacuo at 50° C. for 1.5 h. 6.87 g (81%) of the target compound were isolated and were employed without further purification in the next stage.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[O:9][CH2:8]1.N1C=CC=CC=1>ClCCl>[CH2:7]1[O:16][C:10]2([CH2:15][CH2:14][N:13]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH2:12][CH2:11]2)[O:9][CH2:8]1
Reactant: CCCC(=O)Cl
Reactant: C1CC2(CCN1)OCCO2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)N1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Butyryl chloride (0.53 g, 5 mmol) in dry dichloromethane (5 ml) was added dropwise with stirring to 4-piperidone ethylene ketal (0.72g, 5 mmol) and pyridine (0.5 ml) in dry dichloromethane (10 ml). The solution was stirred at 20° C. overnight then washed successively with dilute HCl, saturated sodium bicarbonate solution and water and dried (sodium sulphate). Evaporation of the solvent gave the product as a clear syrup (0.66 g). MS (+EI) 213 (M+), 1H NMR (CDCl3) 3.98 (4H, s), 3.70 (2H, t), 3.53 (2H, t), 2.33 (2H, t), 1.61-1.83 (6H, m), 0.97 (3H, t).
Reaction SMILES: [CH:1]([C@H:3]1[C@H:7]2[CH2:8][CH2:9][C:10]3[C:15]([N:6]2[C:5](=[O:17])[O:4]1)=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=3)=[CH2:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.CN(C)C=O>[CH2:24]([O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:6]1[C:5](=[O:17])[O:4][C@@H:3]([CH:1]=[CH2:2])[C@H:7]1[CH2:8][CH2:9]2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C[C@@H]1OC(=O)N2c3ccc(O)cc3CC[C@H]12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: C=C[C@@H]1OC(=O)N2c3ccc(OCc4ccccc4)cc3CC[C@H]12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a mixture of 10 g (0.043 mol) of trans-3-ethenyl-7-hydroxy-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one (obtained in Step 2 of Example 1) and 12 g (0.086 mol) of potassium carbonate in 250 ml of acetonitrile and 50 ml of dimethylformamide are added 8.9 g (0.052 mol) of benzyl bromide. The mixture is stirred at 80° C. for 1 h then filtered while hot and washed with acetonitrile, and the filtrate is evaporated to dryness under reduced pressure. The residue is taken up in ethyl acetate and washed several times with water, and the organic phase is then dried over sodium sulphate and concentrated under reduced pressure. After recrystallization from diisopropyl ether, 12.8 g of product are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:9][C:10]1[CH:15]=[C:14]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[N:6][CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Nc1cncc(Cl)n1
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: Cc1ccccc1
Solvent: CCO
Product: Nc1cncc(-c2cccc(F)c2)n1
Reaction time: 4 h
Yield: 95.6 %

Procedure:
To a stirred solution of 2-amino-6-chloropyrazine (2.0 g, 15.43 mmol) in a mixture of toluene (90 mL) and ethanol (8.5 mL) was added 3-fluorophenyl boronic acid (2.60 g, 18.51 mmol) and a 2M aqueous solution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (0.713 g, 0.617 mmol) was added. The mixture was subjected again to three cycles of evacuation-backfilling with argon the flask was capped and placed in a 110° C. oil bath. After 4 h, the mixture was cooled, partitioned between dichloromethane and water the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexanes to 50% ethyl acetate in hexanes). Concentration in vaccuo of the product-rich fractions provided the titled compound (2.79 g, 95%) as a yellowish solid (2.79 g, 95%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[CH:30][CH:31]=1.N1C(C)=CC=CC=1C>ClCCl.O1CCCC1.CN(C)C=O.C(#N)C>[NH2:33][C:27]1[N:28]=[C:29]([NH:32][C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=2)=[O:10])[CH:30]=[CH:31][C:26]=1[C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: COc1ccc(Cl)c(-c2ccc(N)nc2N)c1
Reactant: CCn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCn1nccc1C(=O)Nc1ccc(-c2cc(OC)ccc2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
To an ice-cooled solution of 1-ethyl-1H-pyrazole-5-carboxylic acid (0.140 g, 1 mmol) in dichloromethane (2 ml) and tetrahydrofuran (2 ml) was added oxalyl chloride (0.262 ml, 3 mmol) followed by 1 drop of dimethylformamide. The reaction was stirred at room temperature for 1 hour before concentration in vacuo. The residue was azeotroped with dichloromethane, dissolved in acetonitrile (4 ml) and 2 ml was added dropwise to a cooled solution of 3-(2-chloro-5-methoxyphenyl)pyridine-2,6-diamine (preparation 1, 0.100 g, 0.4 mmol) and lutidine (0.070 ml, 0.6 mmol) in acetonitrile (4 ml). The reaction was allowed to warm to room temperature and stirred under nitrogen for 72 hours. The reaction was concentrated in vacuo and partitioned between dichloromethane (10 ml) and water (10 ml). The organic was dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethylacetate:heptane 1:3 to 3:1 to furnish 30 mg white solid as the desired compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:21][C:22](OC)=[O:23])[CH:14]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:16]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][OH:23])[CH:14]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:16]=1
Reactant: COCOc1cc(CC(=O)OC)cc(OCOC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc(CCO)cc(OCOC)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of lithium aluminum hydride (1.0 g, 26 mmol) in tetrahydrofuran (50 mL) was cooled to 4° C., and a solution of methyl 3,5-bis(methoxymethoxy)phenylacetate (5.3 g, 20 mmol) obtained in Example 1, Step 1 in tetrahydrofuran (50 mL) was added dropwise thereto, followed by stirring at 4° C. for 30 minutes. To the reaction mixture was added anhydrous sodium sulfate decahydrate to stop the reaction, and the mixture was stirred at room temperature for 12 hours. The resulting suspension was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/1) to obtain 2-[3,5-bis(methoxymethoxy)phenyl]ethanol (4.6 g, 98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[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]>>[O:23]=[C:14]1[C:15]2[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:18])[N:13]1[O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCO
Product: CC(C)(C)OC(=O)NCCON1C(=O)c2ccccc2C1=O

Procedure:
tert-Butyl 2-(1,3-dioxoisoindolin-2-yloxy)ethylcarbamate 2E was prepared with quantitative yield from tert-butyl 2-hydroxyethylcarbamate and N-hydroxyphthalimide by a procedure analogous to Example 2A, Step 1. ESI-MS: m/z 329.3 (M+Na)+.