Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([NH:17][CH:18]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:32])([F:31])[F:30])[CH:9]=2)[N:4]=1)#[N:2].C1(SC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl.CCOCC>[NH:20]1[CH2:21][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:29]([F:32])([F:31])[F:30])[CH:9]=3)[N:4]=[C:3]([C:1]#[N:2])[CH:12]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cc(C#N)nc3ccc(C(F)(F)F)cc23)C1
Solvent: CSc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: N#Cc1cc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc2n1
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl 3-(2-((2-cyano-6-(trifluoromethyl)quinolin-4-yl)amino)acetamido)azetidine-1-carboxylate (3.35 g, 7.45 mmol) from above step E, in DCM (50 mL) was treated with thioanisole (0.25 mL, 2 mmol) and stirred for 10 min and then treated with trifluoroacetic acid (50 mL) dropwise. The resulting opaque solution was stirred for 2.5 h at room temperature and diluted with Et2O (200 mL). Precipitate was formed. This mixture was cooled in the refrigerator and the solvent decanted (solid sticks to the flask). The solid was dried under high vacuum and recrystallized from iPrOH to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Yield: 83.1 %

Procedure:
Methyl 3-chloro-4-iso-propoxybenzoate (5.5 g, 24.1 mmol) was hydrolysed using 1M NaOH (36 ml) in methanol (80 ml). Extraction and work-up with ethyl acetate gave the title compound (4.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[NH:43]1[C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[CH2:45][C@H:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[C:10]([N:43]1[C:47]2=[N:48][CH:49]=[CH:50][CH:51]=[C:46]2[CH2:45][C@H:44]1[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (270 mg, 1.04 mmol, Eq: 1.00) was combined with DCM (10 mL) to give a colorless solution. Diisopropylethylamine (0.73 mL, 4.16 mmol, Eq: 4) was added followed by N,N,N′,N′-tetramethylfluoroformamidinium hexafluorophosphate (824 mg, 3.12 mmol, Eq: 3). The reaction was stirred at rt for 1 h and then (S)-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (200 mg, 1.04 mmol, Eq: 1.00) was added. After stirring overnight at rt, the reaction mixture was washed with saturated aqueous NaHCO3 (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 24 g, 0% to 30% EtOAc in hexanes) to give (S)-ethyl 1-((S)-2-(tert-butoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (220 mg), m/z=434 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:26]=[C:27]([C:31]([OH:33])=O)[NH:28][C:29]=1[CH3:30].Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:43]=[C:44]([CH:48]=[C:49]([Cl:51])[N:50]=2)[C:45]([NH2:47])=[O:46])[CH2:38][CH2:37]1>CN(C=O)C>[Cl:51][C:49]1[CH:48]=[C:44]([CH:43]=[C:42]([N:39]2[CH2:40][CH2:41][CH:36]([NH:35][C:31]([C:27]3[NH:28][C:29]([CH3:30])=[C:25]([Cl:24])[CH:26]=3)=[O:33])[CH2:37][CH2:38]2)[N:50]=1)[C:45]([NH2:47])=[O:46]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: Cc1[nH]c(C(=O)O)cc1Cl
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)cc1Cl

Procedure:
Diisopropylethylamine (0.34 ml, 2.0 mmol), EDC (0.121 g, 0.63 mmol) and HOAT (0.086 g, 0.63 mmol) were added to a stirred solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 8, 0.1 g, 0.63 mmol) in DMF (2 ml) at room temperature. The resultant solution was stirred for 15 mins then a solution of 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70, 0.19 g, 0.75 mmol) in 3 ml of DMF was added. The reaction was concentrated after 2 hours and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were washed with 1 N HCl, water and brine, then dried over magnesium sulfate and concentrated under vacuum. The residue was purified by reverse phase chromatography (water/acetonitrile gradient, 20-95%) to give the title product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH2:20])=[C:15]2[CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+].O.Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:21][CH3:22])[C:19]([NH:20][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[C:15]2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(N)c(SC)nn12
Reactant: Brc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(Nc3ccccn3)c(SC)nn12
Temperature: 120 °C
Reaction time: 5 h

Procedure:
After dissolving [7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (40 mg) in toluene (1 mL), 2-bromopyridine (0.013 mL), sodium t-butoxide (25 mg) and dichlorobis(tri-o-tolylphosphine)palladium complex (3 mg) were added and the mixture was heated and stirred at 120° C. for 5 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (12 mg) was obtained from the ethyl acetate:n-hexane (1:2) fraction as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([O:6][C:7]2[S:11][N:10]=[C:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]=2[C:20]#[N:21])=[C:4]([CH3:25])[CH:3]=1.CO[CH:28](OC)[N:29]([CH3:32])[CH2:30][CH3:31]>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:9]2[C:8]([C:20]#[N:21])=[C:7]([O:6][C:5]3[C:4]([CH3:25])=[CH:3][C:2]([N:1]=[CH:28][N:29]([CH2:30][CH3:31])[CH3:32])=[C:23]([CH3:24])[CH:22]=3)[S:11][N:10]=2)=[CH:18][CH:17]=1
Reactant: Cc1cc(Oc2snc(Cc3ccc(Cl)cc3)c2C#N)c(C)cc1N
Reactant: CCN(C)C(OC)OC
Solvent: Cc1ccccc1
Product: CCN(C)C=Nc1cc(C)c(Oc2snc(Cc3ccc(Cl)cc3)c2C#N)cc1C
Reaction time: 22 h

Procedure:
A solution of 1.80 g (4.87 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-3-(4-chlorobenzyl)isothiazole-4-carbonitrile and 0.91 g (6.8 mmol) of N-(dimethoxymethyl)-N-methylethanamine in 60 ml of toluene is stirred at 80° C. for 22 h. Another 0.91 g (6.8 mmol) of N-(dimethoxymethyl)-N-methylethanamine is added, and the solution is then stirred for a further 22 h.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[N+:27]([C:26]1[CH:21]=[CH:22][C:23]([O:17][C:16]([C:15]2[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:11][C:10]=3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)=[O:18])=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: COc1ccc(C(=O)O)c2sc(N3CCCCC3)nc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCCCC3)nc12
Yield: 89.3 %

Procedure:
Starting from 2-(piperidin-1-yl)-4-methoxybenzothiazole-7-carboxylic acid (190 mg), p-nitrophenol (100 mg), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (150 mg) in dichloromethane (20 ml). Purification by column chromatography (eluent 50% ethylacetate in hexane) yielded the title compound as an off-white solid (240 mg). TLC Rf 0.39 (50% ethyl acetate in hexane).
Reaction SMILES: [N+:1](=[C:3]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6][N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[C:4]1=[O:22])=[N-:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.C(=O)(O)[O-].[Na+]>C(#N)C.[Cl-].[Na+].O.O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:5]1[C:4](=[O:22])[C:3](=[N:1][NH2:2])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[N:6]1
Reactant: [N-]=[N+]=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: NN=C1C(=O)N(c2ccccc2F)N=C1c1ccccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Diazo-2,5-bis(2-fluorophenyl)-2,4-dihydro-3H-pyrazol-3-one [(Example 18, Step 2) 213 mg, 0.714 mmol] was dissolved in acetonitrile (10 mL) and treated with triphenylphosphine (225 mg, 0.857 mmol, 1.2 equiv). After stirring for 30 minutes at ambient temperature, the mixture was treated with methanol (5 mL) and water (5 mL) and warmed to 60° C. for 1 hour. The mixture was cooled to ambient temperature, poured into brine (50 mL) and sodium bicarbonate (20 mL, aqueous saturated) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [BrH:1].[CH:2]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]2[CH:16]=1)([CH3:4])[CH3:3].[H][H]>[Pd].CO>[BrH:1].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([CH:16]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:6]=2)[CH:9]=1
Reactant: [H][H]
Reactant: CC(C)c1cn2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Agent: Br
Solvent: CO
Product: CC(C)c1cn2cc(N)ccc2n1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a methanol solution (20 ml) containing 2-isopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide (280 mg), 10% palladium-on-carbon (30 mg) was added, and inside the reaction system was substituted with hydrogen, followed by an hour's stirring at room temperature. The reaction liquid was filtered through Celite™. Concentrating the filtrate under reduced pressure, crude 6-amino-2-isopropylimidazo[1,2-a]pyridine hydrobromide (250 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=[O:14].[NH2:28][C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1>C(O)C.C(N(CC)CC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=1)[CH:6]=[C:5]2[C:13]([NH:15][C:16]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][O:19][C:20]=1[CH3:21])=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Cl)nc2ccc(Br)cc12
Reactant: Nc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Nc2cccc(O)c2)nc2ccc(Br)cc12
Yield: 85.9 %

Procedure:
The solution of 6-bromo-2-chloro-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (50 mg) and 3-aminophenol (50 mg) in ethanol (2 mL) and triethylamine (0.1 mL) was microwaved at 170° C. for one hour. The reaction mixture was then diluted with ethyl acetate (60 mL). The organic solution was washed with water (60 mL), 1N HCl aqueous solution (2×60 mL), separated, dried, evaporated and re-crystallized from ethyl acetate and hexanes to give 6-bromo-2-(3-hydroxyphenyl)amino-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (50 mg) as a yellow solid. 1H NMR (acetone-d6): δ 2.53 (s, 3H), 6.72 (d, J=6.9 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.51 (m, 4H), 7.60 (s, 1H), 7.78 (m, 3H), 7.87 (d, J=9.0 Hz, 1H), 8.15 (d, J=2.1 Hz, 1H), 8.70 (br, 1H), 9.77 (br, 1H); LCMS: ret. time: 25.49 min.; purity: 1100%; MS (m/e): 514.91 (M+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9].Cl.C[N:18]1[CH2:23][CH2:22][C@H:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[C@H:20]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:19]1>C1C=CC=CC=1>[C:35]1([C@H:20]2[C@@H:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=3)[CH2:22][CH2:23][N:18]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[CH2:19]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CN1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2ccc(C(F)(F)F)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.46 g of anhydrous potassium carbonate and 0.5 ml of 2,2,2-trichloroethyl chloroformate are added under nitrogen to a solution of 1.11 g of the free base of cis-1-methyl-3-phenyl-4-(4-trifluoromethylphenoxy)piperidine of Example 22 in 10 ml of dry benzene. After 1 hour at room temperature the mixture is refluxed 18 hours. Another 0.045 ml of 2,2,2-trichloroethyl chloroformate is added, the mixture is again refluxed 18 hours, then cooled and partitioned between ether and water. The organic phase is washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to an oil. This material is dissolved in benzene and filtered through a column of silica gel, then is further purified by preparative chromatography on five 2 mm silica preparative plates, using 3:1 petroleum ether as solvent. A nearly colorless glass of cis-3-phenyl-1-(2,2,2-trichloroethoxycarbonyl)-4-(4-trifluoromethylphenoxy)piperidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.B.Cl>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][OH:7])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: OCc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloronicotinic acid (3.0 g, 18.98 mmol) is dissolved in 30 ml of tetrahydrofuran (THF), with the temperature of the solution maintained below 30°. A 1 M solution of borane/TMF (19 ml, 19.0 mmol) is added at a rate to maintain a slow evolution of gas. This mixture is stirred at RT overnight. The reaction is poured onto approximately 50 g ice with 2 ml concentrated hydrochloric acid and is stirred for 1 hour. The pH of the reaction is adjusted to 5. The reaction is then extracted with chloroform, washed with water, dried and stripped to give 6-chloro-3-pyridinemethanol. A mixture of this pyridinemethanol (2.5 g, 17.4 mmol) and 1-fluoro- 4-nitrobenzene (2.4 g, 17.4 mmol), dissolved together in 15 ml of THF, is added to a stirring suspension of sodium hydride (0.42 g, 17.4 mmol) in 25 ml of THF at a rate to maintain the temperature below 32° . The mixture is stirred for 1 hour, then diluted with water, extracted with chloroform, washed with water, dried and stripped to give 2-chloro-5-(4-nitrophenoxy)methylpyridine.
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:25][C@@H:15]2[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]2)=[CH:22][CH:21]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3)O2)cc1
Yield: 74.9 %

Procedure:
3 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.91 g of p-chlorobenzyl alcohol were dissolved in 40 ml of diethyl ether, and 2-3 drops of phosphorus oxytrichloride were added to the resulting solution. The mixture was then allowed to react at room temperature for 1.5 days, after which 2 drops of triethylamine were added and the mixture was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 8:1 by volume mixture of hexane and ethyl acetate, to give 3.44 g of trans-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 0.59 g of cis-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 0.86 g of an approximately 1:1 cis/trans mixture.
Reaction SMILES: [C:1](=O)([O-:4])[O:2]C.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[O:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:18][CH:19]=1)=[O:14]>CN(C)C=O>[CH2:21]([O:20][C:17]1[O:16][C:15]([C:13]([CH2:12][C:1]([OH:4])=[O:2])=[O:14])=[CH:19][CH:18]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(C)=O)o1
Reactant: COC(=O)[O-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)CC(=O)O)o1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of magnesium methyl carbonate in dimethyl formamide (300 g of a 2.0 mM/g solution) is heated in a 120° C oil bath with stirring under carbon dioxide flushing for 1/2 hour. To this mixture is added 32.3 g (0.100 mole) of 5-(tetradecyloxy)-2-furyl methyl ketone, and the oil bath temperature is raised to 130° C to 150° C. Dry nitrogen is flushed through the mixture for 5 hours. The mixture is allowed to cool to room temperature under carbon dioxide flushing after which it is poured slowly into 2 liters of concentrated HCl-ice (1:1) with vigorous stirring. When the evolution of gas is complete the precipitate is collected and washed with cold water, then dried to give 2-[5-(tetradecyloxy)-2-furoyl]acetic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[S:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].O.[C:28](=O)(O)[O-].[Na+].IC>C(O)C>[CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18]([S:24][CH3:28])=[N:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CI
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)nc1SC
Reaction time: 24 h

Procedure:
The product of step (iii) (0.58 g) was dissolved in ethanol (30 ml) and water (5 ml) and treated with sodium bicarbonate(0.14 g) and iodomethane (0.2 ml) and stirred for 24 hours. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4) and solvent evaporated under reduced pressure. The residue was triturated with isohexane and filtered to give the product. Yield 0.41 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].CS(O[CH:14]1[CH2:27][C:16]2([CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)[CH2:15]1)(=O)=O.[NH4+].[Cl-]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:14]2[CH2:27][C:16]3([CH2:19][N:18]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:17]3)[CH2:15]2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(OS(C)(=O)=O)C2)C1
Reactant: Brc1cn[nH]c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2(CC(n3cc(Br)cn3)C2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
To a solution of 4-bromopyrazole (111 mg, 0.755 mmol) in DMF (dry, 2.5 mL) was added NaH (60 wt % in oil, 33 mg, 0.82 mmol) in portions at 0° C. under N2. The mixture was stirred at 0° C. for 15 min, the ice-bath was removed. The mixture was stirred at room temperature for 90 min. tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.686 mmol) was added in one portion. The mixture was stirred at room temperature for 1 h, then 80° C. for 18 hrs. The mixture was concentrated in vacuo to give the residue which was dissolved in DCM (30 mL). A saturated solution of NH4Cl (30 mL) was added. The layers were separated. The aqueous phase was extracted with DCM (2×30 mL). The combined organic phase was dried over anhydrous Na2SO4 and then concentrated to give the crude residue which was purified by CombiFlash (40 g silica gel column, Hexane/EtOAc) to afford tert-butyl 6-(4-bromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (74 mg, 31%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27](B(O)O)[CH:28]=2)[CH:23]=[N:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.ClCCl.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>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[CH:28]=2)[CH:23]=[N:22]1
Reactant: OB(O)c1ccc2cn[nH]c2c1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccc4cn[nH]c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 78.3 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 200.0 mg, 0.68 mmol) in 1,4-dioxane (1 mL) was added 1H-indazol-6-ylboronic acid (386.0 mg, 2.38 mmol), K3PO4 (434.0 mg, 2.05 mmol), Pd(PPh3)4 (39.0 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 20 min at 90° C., the reaction mixture was dissolved in dichloromethane (30 mL), washed with water (3×20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 1%-10% ethyl acetate in petroleum ether to afford methyl 2-(1H-indazol-6-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a light yellow solid (200 mg, 78%).