Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH:8]([CH3:10])[CH3:9])=[O:7].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C.CCOCC>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:5][C:6](=[O:7])[CH:8]([CH3:10])[CH3:9])=[CH:14][CH:13]=1
Reactant: CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)C(=O)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
A sodium ethoxide solution (21% by weight in EtOH, 4.86 gm, 15 mmol) was added to a mixture of methylisopropylketone (8.61 gm, 100 mmol, from Aldrich) and 4-fluorobenzaldehyde (12.411 gm, 100 mmol, from Aldrich) in ethanol (150 ml). The solution was allowed to stir at room temperature for 3 hours. The solvent was evaporated to afford an orange oil. The oil was dissolved in ether, washed with saturated NH4Cl and brine, then dried over Na2SO4, filtered and concentrated to give an orange oil. The oil was purified by distillation (bp=106° C. at 1.3 mm Hg) to afford the title compound as a pale yellow oil (10.118 gm, 53%).
Reaction SMILES: CN(C=[O:5])C.FC1C(O)=C(F)C(F)=C(F)C=1F.[CH:18]1([N:24]=[C:25]=[N:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[C:25]([NH:24][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)([NH:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:5]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C=O
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
Suspended in 200 ml of acetonitrile are N-(9-fluorenylmethoxycarbonyl)-4-L-hydroxyproline (20.5 g, 50 mmol), followed by the addition of 12 ml of N, N'-dimethylformamide under ice cooling. The resulting mixture is stirred, to which 11.9 g (1.1 equivalents) of pentafluorophenol and 13.2 g (1.1 equivalents) of dicyclohexylcarbodiimide are added. The resulting suspension is stirred for one hour and then, stirred overnight at room temperature. Dicyclohexylurea produced by the reaction is removed by filtration and the filtrate is concentrated. The concentrate is dissolved in ethyl acetate. Dicyclohexylurea, which remained undissolved, is removed by filtration. The operations of dissolution in ethyl acetate, filtration, and concentration are additionally repeated twice. N,N'-Dimethylformamide contained in the concentrate is completely distilled off under reduced pressure. The concentrate is dissolved in ethyl acetate, and to the resulting solution is added n-hexane for re-precipitation, whereby 28.0 g of the product is obtained (yield: 93%).
Reaction SMILES: [CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1>CCCCCC.C(OCC)(=O)C>[CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(O)CCCCC1CCSS1
Temperature: -7.5 °C
Yield: 77.1 %

Procedure:
A solution which contained 17.5 g R-(+)-thioctic acid and 2.5 g S-(-)-thioctic acid in a mixture of 200 ml n-hexane and 57 ml ethyl acetate was cooled off from 35 to 40° C. down to -5 to -10° C., filtered and dried. 13.5 g thioctic acid were obtained in the novel modification as first crystallizate. The R-(+)-thioctic acid content was 82.6% with a melting range of 47 to 52° C.
Reaction SMILES: C([NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl>>[NH2:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:11]([F:17])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: Nc1c(C(=O)O)cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2-Acetamido-5-fluoro-3-nitrobenzoic acid (200 mg, 0.83 mmol) was added to 3N hydrochloric acid (4.0 mL) and the solution allowed to reflux for 7 hours whereby the solution contained a bright yellow precipitate. The reaction was cooled to room temperature and the precipitate collected and dried to produce 2-amino-5-fluoro-3-nitrobenzoic acid (152 mg, 92%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>CC1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:3]1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 152 parts of 3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzene were added dropwise 218 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux. After cooling the reaction mixture was washed with water and hydrochloric acid, dried, filtered and evaporated. The residue was distilled, yielding 120.5 parts (83%) of ethyl 3-methyl-4-oxo-1-piperidinecarboxylate; bp. 98°-105° C. at 1 mm pressure (intermediate 26).
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:15]([N+:20]([O-])=O)[CH:16]=[N:17]2)=[CH:12][CH:11]=1>O.C(O)(C)C>[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:15]([NH2:20])[CH:16]=[N:17]2)=[CH:12][CH:11]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Temperature: 25 °C
Yield: 135.6 %

Procedure:
A solution of Na2S2O4 (193 g) in H2O (1 L) was added to a boiling solution of (7-bromo-3-nitroquinolin-4-yl)isobutylamine (32.0 g, 99 mmol) in isopropanol (1 L). Upon complete addition, the reaction mixture was cooled to room temperature and the bulk of the isopropanol was removed on a rotary evaporator. The resulting mixture was extracted with CH2Cl2 (3×), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford 39.5 g of the crude 7-bromo-N4-isobutylquinoline-3,4-diamine as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6](O)[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]=[CH:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: OC1CCOc2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2c(c1)OCC=C2
Yield: 13.3 %

Procedure:
A reaction vessel charged with 0.5 gram (0.03 mole) of 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran and 0.02 gram (catalyst) of p-toluenesulfonic acid in 50 mL of toluene was fitted with a Soxhlet extractor containing molecular sieves (3-4 angstrom). The stirred contents of the reaction vessel was heated at reflux for 90 minutes, during which time the water by-product was collected on the molecular sieves. The reaction mixture was combined with the reaction mixture of another preparation of this compound and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, with 1:9 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.6 gram of 7-fluoro-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]([F:13])([F:12])C(O)=O.CN(C=O)C.[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([OH:26])[CH:25]=1>O>[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([O:26][CH:8]([F:12])[F:13])[CH:25]=1
Reactant: Oc1cncc(Br)c1
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1cncc(Br)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Potassium carbonate (7.13 g) and chlorodifluoroacetic acid (1.75 ml) were added to a DMF solution (40 ml) of 3-bromo-5-hydroxypyridine (3.0 g). The temperature of the obtained mixture was heated to 100° C., and the mixture was then stirred for 24 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with diethyl ether. The organic layer was successively washed with a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and was then dried over magnesium sulfate, followed by filtration. The solvent was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:diethyl ether), so as to obtain the title compound (670 mg).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=O)[NH:13][CH:12]=[N:11][C:10]=3[O:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:33])=O>C1C=CC=CC=1>[Cl:33][C:14]1[C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][CH:22]=3)[O:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: O=c1[nH]cnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Into a 50 mL round bottom flask was placed 5-phenyl-6-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)furo[2,3-d]pyrimidin-4 (3H)-one 46 (132 mg, 0.329 mmol), and benzene (40 mL). The flask was equipped with a magnetic stir bar, dean-stark trap and a reflux condenser. The reaction was brought to reflux with some of the solvent having been distilled into the dean-stark trap. The reaction was allowed to cool to room temperature and phosphorous oxychloride (300 mg, 1.96 mmol) was added dropwise. The reaction was heated at reflux for 20 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C1C(=O)N([I:18])C(=O)C1>>[Cl:1][C:2]1[C:7]([I:18])=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: CCc1cc(Cl)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Product: CCc1nc(N)nc(Cl)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 2.5 g (16 mmol) 4-chloro-6-ethyl-pyrimidin-2-ylamine and 3.7 g (16 mmol) NIS. Yield after precipitation from the reaction mixture: 3.83 g (85%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][O:7][CH3:8])=[O:5].[Cl:13][C:14]1[CH:19]=[C:18](I)[C:17]([Cl:21])=[CH:16][N:15]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([NH:6][O:7][CH3:8])=[O:5])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: CONC(=O)c1ccccc1N
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 24 h
Yield: 33.2 %

Procedure:
Palladium acetate (0.071 g, 0.32 mmol) was added under a nitrogen atmosphere to 2-amino-N-methoxybenzamide (1.32 g, 7.94 mmol) in dioxane (80 mL) containing 2,5-dichloro-4-iodopyridine (2.176 g, 7.94 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.276 g, 0.48 mmol) and cesium carbonate (5.18 g, 15.89 mmol). The resulting suspension was heated at 80° C. for 18 hours and then at 85° C. for a further 24 hours. The mixture was filtered through Celite and then concentrated in vacuo. The residue was diluted with MeOH and then loaded onto an SCX column. The mixture was eluted first with MeOH and then with a 7N solution of NH3 in MeOH. Fractions containing product were combined and then evaporated. The residue was triturated with Et2O to leave 2-[(2,5-dichloropyridin-4-yl)amino]-N-methoxybenzamide (0.823 g, 33% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.66 (3H, s), 7.02 (1H, s), 7.26 (1H, m), 7.38 (1H, m), 7.56-7.64 (2H, m), 8.27 (1H, s), 9.66 (1H, s), 11.88 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=311.93 and 313.96 and 315.92.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH2:21]([S:24](Cl)(=[O:26])=[O:25])[CH2:22][CH3:23]>C(Cl)Cl>[CH2:21]([S:24]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:26])=[O:25])[CH2:22][CH3:23]
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring ice-cold solution of tert-butyl piperazine-1-carboxylate (1, 10.0 g, 53.69 mmol) and Et3N (22.4 mL, 161.07 mmol) in CH2Cl2 (200 mL) was slowly added 1-propanesulfonyl chloride (7.65 g, 53.69 mmol). The mixture stirred at ambient temperature under an atmosphere of nitrogen for 3 h. The mixture was washed with 2 N NaOH (50 mL), 2 N HCl (50 mL), H2O (50 mL), brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford tert-butyl 4-(propylsulfonyl)piperazine-1-carboxylate (2) as an off-white solid (15.70 g, quantitative): 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=1.7 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 7.21 (m, 1H), 7.14 (s, 1H), 7.09 (s, 1H), 3.96 (s, 3H), 3.75 (s, 3H); MS (ESI+) m/z 293.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2].[OH:19][CH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][NH2:27])[CH2:22][CH2:21]1>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:27][CH2:26][CH:23]4[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3cc(OC)ccc3nc21
Reactant: NCC1CCC(O)CC1
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCC(O)CC3)c3cc(OC)ccc3nc21
Temperature: 110 °C
Yield: 32.8 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-methoxy-1H-pyrazolo[3,4-b]quinoline (2.02 g, 15.5 mmol), DMSO (6 ml) and 4-hydroxy cyclohexylmethylamine (2 g, 15.5 mmol) is heated at 110° C. overnight. The reaction mixture is partitioned between CH2Cl2 /water/NaHCO3, and the CH2Cl2 layer is separated, dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to afford 1.8 g of 1-ethyl-6-methoxy-N-(4-hydroxycyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12]([CH2:13]C3C=CC(OC)=CC=3)[C:11](=[O:22])[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.CO[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H-].[Na+]>CN(C)C=O.[Cl-].[NH4+].C(OCC)(=O)C>[C:31]([C@H:10]1[CH2:9][CH:8]([CH2:7][C:4]2[CH:5]=[CH:6][C:1]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:2][CH:3]=2)[N:12]([CH2:13][N:12]2[CH2:8][CH2:9][CH2:10][CH2:11]2)[C:11]1=[O:22])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(CN2C(=O)CC[C@H]2Cc2ccc(-c3ccccc3)cc2)cc1
Reactant: COC(=O)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)[C@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(CN2CCCC2)C1=O
Temperature: 20 °C

Procedure:
Under N2, the mixture of (S)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethylpyrrolidin-2-one (3a, R1=pyrrolidinylmethyl) (1.34 g, 4 mmol) and Benzoic acid methyl ester (0.6 g, 4.4 mmol) in 4 mL dimethylformamide is stirring at 20° C., sodium hydride (55% in mineral oil, 0.23 g, 5.2 mmol) was added, and stirred overnight at 110° C. the reaction mixture is diluted with 5 mL saturated aqueous ammonium chloride solution and 10 mL ethyl acetate, stirred for 15 min, stop stirring, and remove the lower aqueous layer. the organic phase is concentrated to dryness, the residue was purified by column chromatography(ethyl acetate/heptane=1/1) to give (R/S)-3-Benzoyl-(R)-5-biphenyl-4-ylmethyl-1-pyrrolidin-1-ylmethyl-pyrrolidin-2-one (4a, R1=pyrrolidinylmethyl, R4=phenyl), the ratio of (3S,5R) and (3R,5R) is 60:40 as determined by HPLC. Spectroscopic data as Example 6, Method 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1>CO.[Ni]>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:11])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(Cl)nc(Cl)c1N
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloro-3-nitro-pyridin-4-amine (2.6 g, 14.4 mmol) from Step A in MeOH (150 mL) was added Raney Nickel catalyst (2 g) and the reaction agitated under a hydrogen atmosphere in a Parr apparatus (35 p.s.i.) for 2 h. The reaction mixture was filtered through a pad of Celite and concentrated to yield the title compound. MS: m/z=178 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(Cl)(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
[7-(Methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (2.31 g, 10.65 mmol) and 1,1-dimethylethyl 4-piperidinylcarbamate (3.15 g, 15.98 mmol) were stirred in a 1:1 mixture of chloroform and methanol (140 ml) for 1 h at rt under argon. This mixture was then treated with NaBH(OAc)3 (10.16 g, 47.93 mmol) and stirred for a further 45 mins. The solvents were then removed from the reaction and crude residues purified by column chromatography on silica gel using a 0-35% MeOH/DCM gradient, to give the desired product (2.0 g; 47%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Solvent: CO
Product: COC(=O)c1cc(N)ccc1C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Methyl 2-methyl-5-nitrobenzoate (5.06 g) was suspended in methanol (100 ml). The mixture was degassed by bubbling nitrogen for 15 minutes. Pd/C 10% wet Degussa type E101 NE/WW (260 mg) was added and the mixture stirred under hydrogen atmosphere (balloon) overnight. The suspension was filtered and the solvents evaporated to afford methyl 5-amino-2-methylbenzoate as an orange oil (4.18 g, 97% yield).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:14][CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[OH:4])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: COCOc1cnccc1CCCO
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtained in Example 2 and triphenylphosphine (4.50 g, 17.0 mmol) are dissolved in THP (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (3.00 g, 15.0 mmol) and 2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is further stirred at 40° C. for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 47% aqueous hydrobromic acid solution (20 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/ethanol), recrystallized from ethanol/diethyl ether to give the title compound (3.10 g) as colorless crystals, m.p. 116-118° C.
Reaction SMILES: [O:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4](O)[CH2:3][CH2:2]1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:1][CH2:2][CH2:3]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CCOc2ncccc21
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NC1CCOc2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (3.31 mmol) in 16.5 mL toluene were added DPPA (4.96 mmol) followed by DBU (4.96 mmol) at 0° C. The cooling bath was removed after 2 h and the mixture was stirred at RT overnight. The reaction was quenched by adding sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired product as colorless oil;
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])=[CH2:6].[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[NH2:15]>ClC1C=CC=CC=1>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:14]=1[N:15]1[CH2:11][CH2:10][S:7](=[O:9])(=[O:8])[CH2:5][CH2:6]1
Reactant: Nc1c(F)cccc1F
Reactant: C=CS(=O)(=O)C=C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=S1(=O)CCN(c2c(F)cccc2F)CC1
Temperature: 110 °C

Procedure:
Aluminum chloride (310 g, 2.3 mol) was added to chlorobenzene (2.5 L) to give a cloudy green suspension. Vinyl sulfone (230 mL, 2.3 mol) was added via funnel, followed by 2,6-difluoroaniline (250 mL, 2.3 mol). The light brown solution was heated to 110° C. Upon completion of the reaction, the heat was removed and the black solution was self-cooled to 70° C. The reaction mixture was then quenched in methylene chloride (4 L) and ice water (5 L), the aqueous phase was extracted with methylene chloride (3 L, 2 L, 2 L, 2 L) and the combined organic layers are concentrated, rediluted with branched octane (3 L), and then cooled to 0° C. for 30 minutes. The solids are filtered and washed with branched octane (2×500 mL) and are then dissolved in methylene chloride (3 L) and loaded onto a SiO2 plug (1.8 kg). The column was eluted with dichloromethane (16 L) until clear. The methylene chloride solution was concentrated, and the solids are dissolved in hot ethyl acetate (3 L) followed by the addition of hexanes (900 mL). The black solution was self-cooled to room temperature overnight, and the resulting light amber crystal needles are filtered and washed with hexanes (4×250 mL). The solids are dried under reduced pressure at 50° C. overnight to give the title compound, 1H NMR (CDCl3) (δ): 7.08 (m, 1H), 6.91 (m, 2H), 3.67 (m, 4H), 3.18 (m, 4H).