Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[H-].[Na+].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:16]([O:18]C)=[O:17]>C1(C)C=CC=CC=1>[CH3:24][O:23][C:21](=[O:22])[C:20](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)[CH:15]([CH3:14])[C:16]([OH:18])=[O:17]
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
After the careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (20 g, 0.5 mol, 60% in mineral oil) in anhydrous toluene (200 mL), a solution of 4-fluoro-benzaldehyde (31 g, 0.25 mol) and dimethyl 2-methyl-succinate (60 g, 0.38 mol) in anhydrous toluene (100 mL) was added at room temperature under a stream of nitrogen. The resulting mixture was stirred at room temperature for 30 minutes and then quenched by the slow addition of water (20 mL). The mixture was acidified to pH 3 by the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (20 g, 33%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ ppm 7.77 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 3.82 (q, 7.2 Hz, 1H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[C:30](Cl)=[O:31]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccc2ccccc2c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-naphthoyl chloride were combined to provide N2-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-naphthamide as a white powder, m.p. 257.0° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.85 (broad s, 2H), 8.69 (broad s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.99-7.80 (m, 5H), 7.75-7.50 (m, 4H), 4.75 (t, J=6.9 Hz, 2H), 3.39 (m, 2H), 1.98 (quintet, J=7.2 Hz, 2H), 1.68 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 409.1909 (409.1903 calcd for C25H23N5O).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:11][CH3:12].C(N(CC)CC)C.[C:21](O)(=[O:23])[CH3:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:21](=[O:23])[CH3:22])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Yield: 84 %

Procedure:
To a mixture of 29.0 g (0.16 mole) of methyl-4-amino-2-methoxybenzoate, 0.5 g of 4-dimethylaminopyridine, and 16.0 gm (0.16 mole) of triethylamine in 500 ml of dichloromethane was added in batches 22 ml (ca. 0.23 mole) of acetic acid. After two hours the reaction mixture was neutralized with sodium bicarbonate (in solution and as a solid). The organic phase was washed successively with aqueous sodium bicarbonate. The organic phase was washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from toluene gave 30 g of methyl-4-acetamido-2-methoxybenzoate. To 100 ml of fuming nitric acid, stirred at -40° C., was slowly added 22.3 g (0.10 mole) of the acetylated intermediate. After about twenty minutes the mixture was warmed to 0° C. and stirred for another twenty minutes. The mixture was poured onto one liter of ice and the resultant precipitate was collected. Recrystallization from toluene/ethanol gave 14.2 g of the nitrated and deacetylated compound, methyl-4-amino-2-methoxy-5-nitrobenzoate. (Under similar conditions in which the acetyl group is not removed, saponification with methanolic sodium hydroxide gives the same product.) Hydrogenation of the nitro intermediate in tetrahydrofuran using Raney nickel as catalyst gave methyl-4,5-diamino-2-methoxybenzoate. A mixture of 4.83 g (24.6 mMol) of the diamine and 7.08 g (49.2 mMol) of potassium ethylxanthate was heated at reflux under argon in 40 ml of water. The resultant product mixture was chromatographed on silica gel to give 1.5 g of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate. (Analysis. Calc'd. for C10H10N2O3S: C, 50.41; H, 4.23; N, 11.76; S, 13.46. Found: C, 50.30; H, 4.19; N, 11.71; S, 13.12.) The title compound was then prepared by the method of Example 1 using 1.19 g (5.0 mMol) of methyl-2-mercapto-5-methoxy-1H-benzimidazole-6-carboxylate instead of 2-mercaptobenzimidazole and 0.97 g (5.5 mMol)of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Anal. Calc'd. for C17H17N3O3S*2HCl: C, 49.05; H,4.60; N, 10.09; S, 7.70; Cl, 17.03. Found: C, 49.37; H, 4.77; N, 9.72; S, 7.43; Cl, 16.77.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH:16]1([C:20]2[C:28]([C:29](=[O:32])[NH:30][CH3:31])=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([CH3:33])[CH:21]=2)[CH2:19][CH2:18][CH2:17]1.CCN=C=NCCCN(C)C.Cl.CCOC(C)=O>CN(C)C1C=CN=CC=1.CN(C)C=O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:24]([C:23]4[C:22]([CH3:33])=[CH:21][C:20]([CH:16]5[CH2:19][CH2:18][CH2:17]5)=[C:28]([CH:27]=4)[C:29]([NH:30][CH3:31])=[O:32])=[O:25])[CH2:12][CH2:11]3)[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: c1cc2ccc(C3CCNCC3)cc2o1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4ccoc4c3)CC2)c(C)cc1C1CCC1
Temperature: 15 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
Into a 25-mL round-bottom flask, was placed a solution of 4-(benzofuran-6-yl)piperidine (compound 63.6) (110 mg, 0.55 mmol), 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 135 mg, 0.55 mmol), EDC.HCl (210 mg, 1.10 mmol) and 4-dimethylaminopyridine (133.5 mg, 1.09 mmol) in N,N-dimethylformamide (3 mL). The resulting solution was stirred for 2 h at 15° C. then diluted EtOAc (60 mL). The resulting mixture was washed with aqueous saturated NH4Cl (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product (110 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (51.0% CH3CN up to 60.0% in 9 min, up to 100.0% in 5 min, down to 51.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (46.0 mg, 20%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:19]
Reactant: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Yield: 89.4 %

Procedure:
To a solution of tert-butyl [({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 89 (0.23 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl [({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]acetate 90 (0.16 g, 89%) as a clear thick oil.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:20]=[C:21]([CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])[S:22][CH:23]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(Cl)Cl.C[O-].[Na+]>CO>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:20]=[C:21]([CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])[S:22][CH:23]=2)=[CH:11]1
Reactant: O=C(NCc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1cc(-c2c[nH]c3ncccc23)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide (0.050 g, 0.000081 mol;) was dissolved in Methylene chloride (3 mL, 0.05 mol;) then 0.5 M of Sodium methoxide in methanol (3 mL) was added and the reaction was heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product at 1.34 477.10. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated. ES (+) MS m/e=477.10; NMR (400 MHz, DMSO-d6) δ ppm 4.72 (m, 2H), 5.21 (s, 2H), 6.60 (t, 1H, J=8 Hz), 7.19 (m, 2H), 7.37-7.50 (m, 3H), 7.62 (s, 1H), 7.86 (m, 1H), 7.64 (s, 1H), 8.24 (m, 1H), 8.41 (m, 1H), 10.04 (t, 1H, J=6 Hz).
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[C:17]([NH:22]C(=O)C)=[CH:16]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O>C(O)(=O)C>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[O:19][C:18](=[O:21])[C:17]([NH2:22])=[CH:16]3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc2cccc(OS(=O)(=O)c3ccccc3)c2oc1=O
Temperature: 50 °C
Yield: 83.5 %

Procedure:
To a solution of the compound produced in the above (1) (3.0 g, 8.3 mmol) in acetic acid (30 mL) was added 50 vol % sulfuric acid (30 mL) followed by stirring at 50° C. After the crystals were completely dissolved, the reaction mixture was allowed to cool and added to water. The crystals separated out therefrom were filtered and dried to give 2.2 g (83%) of the title compound.
Reaction SMILES: C([Li])CCC.[C:6]([Si](C)(C)C)#[CH:7].[O:12]1[CH:16]=[C:15]([C:17](=[O:19])[CH3:18])[N:14]=[CH:13]1>C1COCC1.O>[O:12]1[CH:16]=[C:15]([C:17]([OH:19])([C:6]#[CH:7])[CH3:18])[N:14]=[CH:13]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)c1cocn1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cocn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of n-butyllithium (2.5M in hexane, 1.03 mL, 2.57 mmol) in THF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.34 mL, 2.38 mmol). The reaction was stirred at −78° C. for 10 minutes and then 1-(1,3-oxazol-4-yl)ethanone (220 mg, 1.98 mmol) was added in more THF (2 mL). The reaction was stirred at −78° C. to RT for 1 hr. The mixture was then diluted with water and the volatiles removed. The product was then extracted with EtOAc (2×15 mL) and the combined organics washed with water (2×5 mL) and dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by column chromatography (eluted with 2-13% methanol) to give the title compound; 1H NMR (500 MHz, CDCl3) delta 1.85 (3H, s), 2.61 (1H, s), 2.92 (1H, s), 7.71 (1H, s), 7.87 (1H, s).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([O:19]CC)=O)=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[CH:12]=[N:13][C:14]([C:17]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccc(Br)o3)noc2c1O
Temperature: 25 °C
Yield: 92.2 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (62 mg, 0.176 mmol) was dissolved in 10 mL of DMF. Glycine (0.264 g, 3.51 mmol) and sodium ethoxide (0.179 g, 2.63 mmol) were added and the mixture was refluxed for 3 h. The mixture was cooled to room temperature and diluted with 70 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. The resulting suspension was filtered and the solid was dried under vacuum to give 62 mg of the title compound. MS: (+) m/z 382, 384 (M+1, 79Br/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]=[O:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]([OH:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(-c2cccc(Cl)c2)c2ncccc2c1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc(-c2cccc(Cl)c2)c2ncccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
8-(3-Chlorophenyl)-6-quinolincarbaldehyde (0.8 g) was dissolved in 20 mL of tetrahydrofuran and cooled to -78° C. Methyllithium (4.5 mL, 1.4M) in diethyl ether was added dropwise to the solution over 5 minutes, stirred for 20 minutes, poured into 50 mL of saturated ammonium chloride, and stirred for 5 minutes. The solution was extracted with ethyl acetate (2×75 mL). The extracts were combined and dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (30:70 ethyl acetate:hexanes) to obtain 0.72 g of 8-(3-chlorophenyl)-6-(1-hydroxyethyl)quinoline as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].Cl.[NH2:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14]>O1CCCC1>[CH2:8]([O:7][C:5]([CH2:4][NH:1][C:2]([NH:11][C@@H:12]([CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]([O:15][CH3:16])=[O:14])=[O:3])=[O:6])[CH3:9]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CN=C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
5.13 ml (45.8 mmol) of ethyl isocyanatoacetate are added dropwise to a suspension of 10 g (45.8 mmol) of the compound (3.3) in 100 ml of tetrahydrofuran and the mixture is left to stir at room temperature for 3 h; the solvent is removed in vacuo and the residue is chromatographed through silica gel using ethyl acetate/methanol=20/1. 13.44 g (85%) of (3.4) are obtained as a pale yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].[OH-].C[Sn+](C)C>ClCCCl>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:10]1[N:9]2[CH:20]=[N:21][CH:22]=[C:8]2[CH:7]=[N:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: C[Sn+](C)C
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 85 °C
Yield: 97.6 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (140 mg, 0.34 mmol) in anhydrous 1,2-dichloroethane (2.5 mL) was added trimethyltin hydroxide (215 mg, 1.19 mmol, 3.5 eq.). The reaction mixture was heated at 85° C. for 1 hour and then cooled to RT. The reaction mixture was concentrated in vacuo, and the crude residue was diluted with ethyl acetate. The organic layer was washed with 1N HCl (3×), water and brine, dried (Na2SO4), filtered and concentrated in vacuo. Crystallization from dichloromethane-ether-hexane afforded the title compound as a yellow solid (132.1 mg, 97.7%). 1H NMR (MeOD, 400 MHz) δ ppm 8.76 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.64 (dd, J=10.13, 1.84 Hz, 1H), 7.55-7.50 (m, 1H), 6.72 (t, J=8.49 Hz, 1H); LCMS (method D1): RT=0.77 min, [M+H]=399.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(Tetrahydro-2H-pyran-4-yl)methanol (29.9 mg, 0.257 mmol) was dissolved in dichloromethane (DCM) (4 mL). To this solution was added triethylamine (0.108 mL, 0.772 mmol). The reaction was cooled to 0° C., methanesulfonyl chloride (0.03 mL, 0.386 mmol) added and the reaction left to stir overnight, allowing the reaction to warm to 20° C. The reaction was concentrated in vacuo. The product was partitioned between ethyl acetate (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was dried and concentrated in vacuo, before being used in the next reaction with no further purification or characterisation, 49 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:30]=1[CH3:45].ClC1C=CC2C(=CC=CC=2)N=1>CCOC(C)=O>[CH3:45][C:30]1[C:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:32][C:33]2[C:38]([C:29]=1[N:13]1[C:11]3[C:10](=[CH:9][CH:8]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:12]=3)[C:15]3([CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:14]1)=[CH:37][CH:36]=[CH:35][CH:34]=2
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)nc2ccccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a N2 atmosphere, 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (0.216 g, 0.788 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol) and treated with sodium hydride (0.0208 g, 0.867 mmol). The reaction was allowed to stir at rt for 10 minutes and 4-chloro-3-methyl-2-phenylquinoline (0.100 g, 0.394 mmol) was added. The reaction was placed in a preheated oil bath at 140° C. for 6 h. LCMS showed no starting chloroquinoline remained. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate followed by brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 40% to 60% EtOAc in hexane. The fractions that contained product were further purified by preparative reverse phase chromatography to afford 1-(3-methyl-2-phenyl-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. Mass Spectrum (ESI) m/e=492.3 (M+1) 1H NMR (500 MHz, DMSO-d6) δ ppm 8.06-8.10 (1H, m), 7.80-7.84 (1H, m), 7.74 (1H, ddd, J=8.4, 6.8, 1.5 Hz), 7.64-7.69 (2H, m), 7.48-7.59 (4H, m), 7.11 (1H, d, J=8.3 Hz), 6.27 (1H, dd, J=8.3, 2.2 Hz), 5.58 (1H, d, J=2.2 Hz), 4.01 (1H, d, J=9.8 Hz), 3.83-3.97 (3H, m), 3.56-3.63 (4H, m), 3.48 (2H, tt, J=12.0, 2.1 Hz), 2.82-2.91 (4H, m), 2.22 (3H, s), 1.93-2.05 (2H, m), 1.82-1.88 (1H, m), 1.65-1.73 (1H, m)
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].S([O:9][CH2:10][C@H:11]([OH:14])[CH2:12][OH:13])(C)(=O)=O.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.CS(C)=O.[OH-].[Na+]>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:9][CH2:10][C@@H:11]([OH:14])[CH2:12][OH:13])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CS(=O)(=O)OC[C@H](O)CO
Agent: [CH2-]C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: OC[C@H](O)COc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of sodium hydroxide (39 g) in 200 ml water added to a rapidly stirred solution of (2R)-3-mesyloxy-1,2-propanediol acetonide (172.1 g) and 4-benzyloxyphenol (200 g) in 1.5 L dimethylsulfoxide, and the reaction was heated on a steam bath for 3 hours. The cooled solution was diluted with 1 L 1N sodium hydroxide solution and the resulting solids were washed with dilute sodium hydroxide solution with water. The air-dried solids were taken up in benzene (2 L) and the solution was dried over sodium sulfate, decolorized with charcoal and evaporated in vacuo. The product was dissolved in hot methanol (~1.5 L), cooled to ~40° and filtered free from some non-polar impurity. A small portion of the methanol solution was diluted with water to give (2S)-3-(4-benzyloxyphenoxy)-1,2-propanediol acetonide. Crystallization from hexane furnished the pure specimen, mp 69.5°-71°; [α]D25, +6.26° (c, 1.0, methanol).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][C:17](C(O)=O)=[CH:16][C@H:15]1[OH:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:5][O:4][C:2]([C:17]1[CH2:18][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:12])[C@H:15]([OH:22])[CH:16]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=C[C@H]1O
Reactant: COC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1=C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Methyl chloroformate (29 /ml, 0.37 mol) was added dropwise to a cooled solution (0° C.) of (3R,4S)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid (83 g, 0.34 mol) and triethylamine (52 ml, 0.37 mol) in methanol (600 ml). The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature. After stirring for 14 h, it was apparent that the reaction was incomplete. After cooling to 0° C., triethylamine (30 ml, 0.22 mol) was added, and then methyl chloroformate (15 ml, 0.19 mol) was added dropwise. The reaction was complete after a further 2 h. The reaction mixture was concentrated under vacuum and the residue redissolved in dichloromethane (400 ml). The organic solution was washed sequentially with 1M potassium hydrogen sulfate (aq) (2×200 ml), saturated hydrogen carbonate (2×200 ml) and brine (200 ml) before drying over magnesium sulfate. Following filtration, the solvent was removed to yield an orange oil which was redissolved in methanol (300 ml) and cooled to 5° C. Sodium methoxide (0.25 ml, 25% wt solution in methanol, 3 mol %) was then added and the reaction mixture cooled and stirred for 4 h. The reaction was quenched with glacial acetic acid and concentrated under vacuum, and the residue was redissolved in dichlormethane (300 ml). The organic solution was washed with saturated sodium hydrogen carbonate (100 ml) then brine (100 ml) and dried over magnesium sulfate. Following filtration, the solvent was removed under vacuum to yield the title compound as an orange oil (76 g, 87%).