Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[S:12]1[CH2:16][CH2:15][N:14]2[CH:17]=[C:18]([C:20](OCC)=[O:21])[N:19]=[C:13]12>O>[OH:21][CH2:20][C:18]1[N:19]=[C:13]2[N:14]([CH:17]=1)[CH2:15][CH2:16][S:12]2
Reactant: CCOC(=O)c1cn2c(n1)SCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cn2c(n1)SCC2
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Lithium aluminium hydride (280 mg, 7.3 mmol) was suspended in dry, redistilled THF (20 ml) under argon and treated dropwise with a solution (THF, 20 ml), of ethyl 2,3-dihydroimidazo[2,1-b]thiazole-6-carboxylate (1.32 g, 6.7 mmol). After 2 h, water was added carefully until effervescence ceased when the mixture was filtered through Celite, the filter pad washed with THF and water and the filtrate and washings combined and evaporated to dryness under reduced pressure. The residue was evaporated twice from ethanol to give the title compound as a white solid (1.03 g, 100%); dH (250 MHz; CD3OD) 3.73-3.95 (2H, m), 4.06-4.30 (2H, m), 4.42 (2H, s), 7.04 (1H, s).
Reaction SMILES: C(=[N:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[C:16]=1[F:26])(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:27].O>CCOCC>[ClH:27].[F:26][C:16]1[C:17]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:18][CH:19]=[CH:20][C:15]=1[NH2:14]
Reactant: Fc1c(N=C(c2ccccc2)c2ccccc2)cccc1OC(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Nc1cccc(OC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of benzhydrylidene-(2-fluoro-3-trifluoromethoxy-phenyl)-amine (7.5 g, 20 mmol) in Et2O (40 mL) was added 3N aqueous HCl (10 mL). The reaction mixture was stirred for 4 h at RT, followed by addition of water. The aqueous layer was extracted with Et2O (2×10 mL), the combined organic layers were washed with brine and then dried over MgSO4. After removal of solvent in vacuo, the residue was purified by preparative HPLC (stationary phase: Gimini 300×50 mm, particle size 10 μm; solvent: A H2O+BCH3CN, pressure: 60-70 bar). The product was extracted with Et2O as the free base from the combined fractions. HCl gas was bubbled through the organic phase, and the solvent was removed under vacuum to afford the title compound. Recrystallisation from EtOH/diisopropylether gave a white solid. 1H NMR (D2O, 400 MHz): δ 7.40-7.35 (m, 1H, ArH), 7.32-7.27 (m, 1H, ArH), 7.27-7.19 (m, 1H, ArH). HRMS: 196.03801 [M]+ (calcd. 196.03800 for C7H5F4NO); Anal. Calcd. for C7H5F4NO: C, 36.31; H, 2.61; N, 6.05; Cl, 15.31; F, 32.82. Found: C, 35.78; H, 2.63; N, 6.14; Cl, 15.69; F, 31.99.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].CC(C)([O-])C.[CH3:12][CH:13]([C:19]([CH3:21])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH2:22]([O:24][C:25](=[O:32])[CH2:26][CH2:27][CH2:28][CH2:29]CBr)[CH3:23]>C(O)(C)(C)C>[C:19]([C:13]([CH3:1])([CH2:12][CH2:29][CH2:28][CH2:27][CH2:26][C:25]([O:24][CH2:22][CH3:23])=[O:32])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:20])[CH3:21]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCCCCBr
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC
Temperature: 50 °C
Yield: 72751.2 %

Procedure:
A mixture of 13.4 g (0.12 mol) of potassium tert-butoxide and 100 g of tert-butanol was stirred and heated until the tert-butoxide totally dissolved. The solution was cooled to about 50° C. and 17 g (0.12 mmol) of ethyl 2-methylacetoacetate was added dropwise. Ethyl-6-bromohexanoate (30 g, 0.13 mmol) was then added dropwise and the reaction mixture was stirred and refluxed for 5 hours. The mixture was filtered and the solvent was removed under reduced pressure. The residue was partitioned between 1M HCl and chloroform. The organic layer was dried over magnesium sulfate and purified on silica gel using 1:10 ethyl acetate/hexane as the eluent to yield 25 g (75%) of diethyl 2-acetyl-2-methyloctanedioate (3) as yellow liquid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[SH:65][C:66]1[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=1>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:19][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:65][C:66]1[CH:67]=[N:68][CH:69]=[CH:70][CH:71]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:22])[CH3:34]
Reactant: Sc1cccnc1
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3cccnc3)C[C@H]12
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.579 ml) in dichloromethane (5.21 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate (1.50 g) and 4-(N,N-dimethylamino)pyridine (33.8 mg) in dichloromethane (75.0 ml) at -30° C. To this solution was added a solution of trifluoromethanesulfonic anhydride (0.489 ml) in dichloromethane (9.29 ml) and the mixture was stirred at -30° C. for 20 minutes. N,N-Diisopropyl-N-ethylamine (5.31 ml) and a solution of stannic chloride and hydrochloric acid salts of 3-mercaptopyridine (1.70 g) in N,N-dimethylformamide (15.3 ml) were then added to the mixture and the resultant mixture was allowed to warm to 20° C. over a period of 3 hours. After cooling to 0° C., additional N,N-diisopropyl-N-ethylamine (2.89 ml) and a solution of stannic chloride and hydrochloric acid salts of 3-mercaptopyridine (0.570 g) in N,N-dimethylformamide (5.13 ml) were added to the mixture. The resultant mixture was allowed to warm to 20° C. over a period of an hour and evaporated in vacuo. The residue was dissolved in dichloromethane (250 ml), washed in turn with cold water (x6) and an aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 15% water (150 g), eluting with a mixture of benzene and acetone (50:1 to 8:1). Crystallization from a mixture of dichloromethane and diethyl ether gave 4 -nitrobenzyl (5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(3-pyridylthio)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.9747 g). The mother liquor was purified by column chromatography on silica gel, followed by crystallization to give the same product (0.2680 g) as a pale yellow powder. Total yield is 1.2427 g.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-:23].[Na+].[CH3:25]O>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:23][CH3:25])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [OH-]
Reactant: CCCOc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Reactant: CO
Agent: [Na+]
Product: CCCOc1nc(N)c2nc(OC)n(Cc3ccccc3)c2n1
Yield: 93 %

Procedure:
To 6-amino-9-benzyl-8-bromo-2-propoxypurine (123 mg, 0.339 mmol) in 10 ml of methanol was added 10N aqueous sodium hydroxide (50 ml) and the solution was refluxed under heating for 2 hours. The reaction mixture was concentrated in vacuo to dryness and to the residue was added water. The mixture was extracted with chloroform and the organic layer was dried on sodium sulfate. After removal of the solvent the residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (99 mg, yield 93%).
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[CH2:58][NH:57][CH2:56]2>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:57]4[CH2:56][C:55]5[C:59](=[CH:60][CH:61]=[C:53]([F:52])[CH:54]=5)[CH2:58]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1)N1Cc2ccc(F)cc2C1
Reaction time: 16 h
Yield: 57.5 %

Procedure:
A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 0.80 g) in DCM (10 ml) at rt was treated with 5-fluoroisoindoline (0.101 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1 M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E60) as a white powder (150 mg). MS electrospray (+ion) 395 (MH+). 1H NMR δ (DMSO-d6): 10.60 (1H, s), 7.62 (2H, m), 7.42-7.06 (5H, m), 4.85 (4H, m), 4.66 (1H, m), 3.75-3.55 (1H, m), 3.45-3.20 (2H, m), 2.90 (2H, m), 2.41-1.62 (10H, m).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:12](=[CH2:22])[O:11][C@H:10]1[N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][CH:26]=[N:27][C:28]=2[NH2:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:33][CH2:34][O:35][P:36]([O:40][CH2:41][CH3:42])([CH2:38][OH:39])=[O:37].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClC(Cl)C>[NH2:32][C:28]1[N:27]=[CH:26][N:25]=[C:24]2[C:29]=1[N:30]=[CH:31][N:23]2[C@@H:10]1[O:11][C@:12]([CH3:22])([O:39][CH2:38][P:36](=[O:37])([O:40][CH2:41][CH3:42])[O:35][CH2:34][CH3:33])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:9]1[O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOP(=O)(CO)OCC
Reactant: C=C1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(Cl)Cl
Product: CCOP(=O)(CO[C@@]1(C)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C)OCC
Temperature: 60 °C
Yield: 26.8 %

Procedure:
To a solution of compound 31.2 (280 mg, 0.59 mmol) in dichloroethane (5 mL) was added diethyl (hydroxymethyl) phosphonate (0.22 mL, 1.47 mmol) and pyridinium p-toluene sulfonate (56 mg, 0.29 mmol). The mixture was heated to 60° C. for 1 h and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to give compound 31.3 (102 mg, 16% yield). 1H NMR (300 MHz, CDCl3): δ −0.45 (s, 3H), −0.08 (s, 3H), 0.05 (s, 3H), 0.71 (s, 9H), 0.98 (s, 9H), 1.35 (m, 6H), 1.61 (s, 3H), 3.78 (t, 1H), 3.95 (t, 1H), 4.04 (s, 1H), 4.21 (m, 4H), 4.96 (m, 1H), 6.24 (d, 1H, J=6.7), 8.10 (s, 1H), 8.70 (s, 1H). LRMS (ESI) MH+ C27H52N5O7PSi2 requires 646.9. Found 645.9.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][N:2]=1.CC1(C)CCCC(C)(C)N1.[Li].[O:18]1[C:22]2([CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:25]2([OH:28])[CH2:26][CH2:27][C:22]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:23][CH2:24]2)[N:2]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: c1ccnnc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]
Solvent: C1CCOC1
Product: OC1(c2cccnn2)CCC2(CC1)OCCO2
Reaction time: 0.1 h
Yield: 44 %

Procedure:
To a solution of pyridazine (17.7 mmol, 1.28 mL) in THF (60 mL) was added lithium 2,2,6,6-tetramethylpiperidine (71 mmol, 10 g) at −78° C. The reaction was then stirred for 6 min and 1,4-dioxa-spiro[4.5]decan-8-one (71 mmol, 11 g) was added. The reaction was stirred for 5 h at −78° C. at which point the reaction was quenched using a solution of ethanol, hydrochloric acid and THF (30 mL, 1:1:1). The resulting solution was extracted using EtOAc. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified using flash chromatography to afford the desired alcohol (44%, 1.84 g). MS (M+H)+237.1.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][CH2:5][NH:6][CH2:7][CH:8](OC)OC.[F:19][C:20]([F:25])([F:24])[C:21](O)=[O:22]>O>[F:19][C:20]([F:25])([F:24])[C:21]([N:6]1[CH2:5][CH2:4][C:3]2[C:2]([F:1])=[CH:16][CH:15]=[C:14]([O:17][CH3:18])[C:13]=2[CH2:8][CH2:7]1)=[O:22]
Reactant: COc1ccc(F)c(CCNCC(OC)OC)c1
Reactant: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(F)c2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
N-(2-Fluoro-5-methoxyphenethyl)-2,2-dimethoxyethanamine (3.0 g, 11.7 mmol, 1.0 eq.) was added dropwise to trifluoacetic anhydride (5.2 mL, 37.3 mmol, 3.2 eq.) at −15° C. The reaction mixture was allowed to warm to r.t. and stirred for 25 min. Then, trifluoroacetic acid (9.2 mL, 120.0 mmol, 10.3 eq.) was added and the resulting solution was heated to 40° C. for 18 hours. The reaction mixture was poured in cold water (100 mL). The mixture was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. To a solution under N2 of the residue in AcOEt/EtOH 1:1 (60 mL), palladium on activated carbon (10 wt. %, 400 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 30 fractions of 45 mL, Heptane to Heptane+50% AcOEt) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20]([O:22][C@@H:23]3[CH:28]4[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]4)[CH2:24]3)=[O:21])[C:11]1=2.C(Cl)Cl.CO>C(#N)C>[Cl-:1].[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:20]([O:22][C@@H:23]3[CH:28]4[CH2:27][CH2:26][N+:25]([CH2:2][C:3](=[O:4])[C:5]5[S:6][CH:7]=[CH:8][CH:9]=5)([CH2:30][CH2:29]4)[CH2:24]3)=[O:21])[C:11]1=2
Reactant: O=C(CCl)c1cccs1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1cccc2ccsc12
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(Nc1ccccc1)c1cccc3ccsc13)C2)c1cccs1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
2-Chloro-1-(thiophen-2-yl)ethanone (36.8 mg, 0.23 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetate (C27) (90 mg, 0.23 mmol) in acetonitrile (3 ml). The reaction was stirred at r.t. overnight. The solvent was removed under vacuum, and the crude product was triturated with Et2O. The compound was first purified by preparative HPLC (Eluent: CH3CN/H2O) and then by flash chromatography (DCM/MeOH=95/5) to obtain (3R)-3-(2-(benzo[b]thiophen-7-yl)-2-(phenylamino)acetoxy)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-1-azoniabicyclo[2.2.2]octane chloride (20 mg, 16% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)CC)C>CO>[CH3:11][O:10][C:8]([C:6]1[CH:5]=[C:4]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:14]=2[F:13])[N:3]=[C:2]([Cl:1])[N:7]=1)=[O:9]
Reactant: NCc1ccc(F)cc1F
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(NCc2ccc(F)cc2F)nc(Cl)n1
Reaction time: 1 h
Yield: 45.93 %

Procedure:
A suspension of methyl 2,6-dichloropyrimidine-4-carboxylate (1 g, 4.87 mmol) in methanol (20 ml) was cooled to −20° C., to this 2,4-difluoro benzylamine (0.627 mg, 4.39 mmol) and triethylamine (0.98 mg, 9.74 mmol) were added. The reaction mixture was stirred at same temperature for 1 hr then at room temperature for 4 hrs. Methanol was removed under vacuum. The residue was purified by column chromatography to get the title compound.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[N:18][OH:19])[CH2:12][C:11]1([CH3:21])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[H][H].[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:28])[CH:26]=[CH2:27]>[Pt].CO>[CH2:1]([O:9][N:10]1[C:11]([CH3:20])([CH3:21])[CH2:12][CH:13]([N:18]([CH2:27][CH2:26][C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:28])[OH:19])[CH2:14][C:15]1([CH3:17])[CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=CC(=O)OCCCCCCCCCCCC
Reactant: CCCCCCCCON1C(C)(C)CC(=NO)CC1(C)C
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)CCN(O)C1CC(C)(C)N(OCCCCCCCC)C(C)(C)C1
Yield: 57.8 %

Procedure:
A mixture of 1-octyloxy-2,2,6,6-tetramethylpiperidin-4-one oxime (10.0 g, 35.4 mmol) (a mixture of octyloxy isomers) 5.5 ml of concentrated hydrochloric acid and 130 ml of methanol is subjected to 3 atmospheres of hydrogen over 5% platinum on carbon for 18 hours. The reaction mixture is filtered through celite and then concentrated. The residue is partitioned between ethyl acetate and aqueous potassium carbonate. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate and finally concentrated to a total volume of about 150 ml. Lauryl acrylate (7.7 g, 32 mmol) is added. After a two-hour reaction time, the reaction mixture is concentrated and the crude product purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to yield 10.0 g (52% yield) of a clear oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>ClCCl.C(OCC)(=O)C>[CH:24]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.3 %

Procedure:
A Dess-Martin reagent (7.89 g) was added to a solution of tert-butyl 4-hydroxymethylpiperidine-1-carboxylate (4.00 g) in dichloromethane (40 ml), and the mixture was stirred for 1.5 hours at room temperature. After diluting with ethyl acetate, the reaction solution was washed with a 1% aqueous solution of sodium hydroxide and a brine successively. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to yield tert-butyl 4-formylpiperidine-1-carboxylate (2.43 g) as a colorless oil.
Reaction SMILES: I[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C(O[B:12]1[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]1)(C)C.[Cl-].[Li+].C([Mg+])(C)C.[Cl-].C(O)(=O)C>C1COCC1.CC(OC)(C)C>[CH3:7][C:4]1[CH:3]=[C:2]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)[S:6][N:5]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(I)sn1
Agent: CC(C)[Mg+]
Agent: [Cl-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)sn1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 83.4 %

Procedure:
To a cooled (−25° C.) solution of 5-iodo-3-methylisothiazole (59.5 g, 264 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50.2 g, 270 mmol) in anhydrous THF (300 mL) was added dropwise 1.3 M isopropylmagnesium lithium chloride in THF (218 mL, 283 mmol) at a rate which maintained the temperature at −15° C. to −25° C. The reaction mixture was stirred at −10° C. for 5 minutes after the addition was completed. HPLC analysis indicated that the starting material was consumed. A solution of acetic acid (16.19 mL, 283 mmol) in THF (40 mL) was added slowly to the reaction solution at 0° C. Hexanes (250 mL) and MTBE (150 mL) were sequentially added to the reaction mixture. A solid precipitate was formed, which was filtered off by passing the reaction mixture through a pad of Celite. The filtrate was concentrated via rotary evaporation to afford an oil residue, which was dispersed in MTBE (500 mL) through vigorous stirring. Additional precipitate was formed, which was filtered off using a pad of Celite. The filtrate was again concentrated to an oil, and MTBE (200 mL) was added, which formed additional solid precipitate that was filtered off using a pad of Celite. The process was repeated two more times until no more solid was formed when MTBE was added to the oil residue. The oil was dried in a rotary evaporator under high vacuum overnight with a bath temperature of 20° C., which afforded the title compound as an oil (49.55 g, 83%). 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 12H), 2.56 (s, 3H), 7.41 (s, 1H).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10](OC)=[O:11])[C:5]=12.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][OH:11])[C:5]=12
Reactant: COC(=O)c1cccn2ccnc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1cccn2ccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
To a cold solution of methyl imidazo[1,2-a]pyridine-8-carboxylate (5.55 g, 31.53 mmol, 1 eq) in THF (100 mL) was added LAH in ether (1 M solution in ether, 4 equiv.) and then stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and quenched with water/15% NaOH/water. Reaction mixture was diluted with ethyl acetate and stirred at room temperature for 15 min and then filtered. The solid was washed with ethanol and the organic layers were combined, dried and evaporated to give the alcohol, which was purified by column chromatography to yield the desired product in 40% yield.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([OH:20])=O)[CH:16]=2)[CH:4]=1.C1C=CC2N(O)N=[N:29]C=2C=1.C(Cl)CCl.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C=O)C>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[C:5]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]([NH2:29])=[O:20])[CH:16]=2)[CH:4]=1
Reactant: O=C(O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)Cn1cc(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.8 %

Procedure:
To 2-(4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-1-yl)acetic acid (0.052 g, 0.168 mmol) in DMF (3 mL) were added HOBt (0.029 g, 0.218 mmol), EDC (0.045 g, 0.235 mmol), ammonium chloride (0.045 g, 0.838 mmol), followed by N-ethyl-N-isopropylpropan-2-amine (0.146 mL, 0.838 mmol). The reaction mixture was stirred for 18 hours at room temperature. The crude mixture was subsequently purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID×75 mm column) eluting with a gradient of 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) to give the title compound as white solid (0.016 g, 31%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.84 (s, 2H), 7.33 (br s, 1 H), 7.51-7.68 (m, 2H), 7.75 (s, 1H), 8.23 (d, J=0.76 Hz, 1H), 8.56 (d, J=4.29 Hz, 2H), 13.62 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C13H10F3N5O, 310.1. found 310.