Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:3]1.[CH3:15][NH:16][CH3:17]>N1C=CC=CC=1>[NH2:1][N:2]1[C:7]([N:16]([CH3:17])[CH3:15])=[N:6][C:5](=[O:10])[C:4]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:3]1
Reactant: CSc1nc(=O)c(C(C)(C)C)nn1N
Reactant: CNC
Solvent: c1ccncc1
Product: CN(C)c1nc(=O)c(C(C)(C)C)nn1N
Yield: 81 %

Procedure:
2-Amino-3-methylthio-6-t-butyl-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) was added to a mixture of a 40% aqueous solution of dimethylamine (5 ml) and pyridine (10 ml), and the resulting mixture was heated with reflux for 5 hours. After the reaction was completed, the reaction mixture was evaporated to dryness under reduced pressure to give a crude product. Recrystallization of the crude product from acetone gave 0.8 g of 2-amino-3-dimethylamino-6-t-butyl-5-oxo-2,5-dihydro-1,2,4-triazine in 81% yield. M.P. 168°-169° C.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn](CCCC)(CCCC)[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])CCC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:28]#[C:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCCC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC#Cc1c(F)c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c12
Yield: 36.7 %

Procedure:
1.9 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 3.5 g of 1-tributylstannyl-hex-1-ine and 0.29 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 8 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is concentrated, the residue is stirred with 30 ml of hexane, and the resulting solid is recrystallised from cyclohexane. 0.7 g of ethyl 1-cyclopropyl-6,7-difluoro-8-(1-hexinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate is obtained (36% of theory).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=O)C>O.N>[SH:4][CH2:5][CH:6]([CH3:21])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])=[O:8]
Reactant: CC(=O)SCC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: N
Solvent: O
Product: CC(CS)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
Nα-(3-Acetylthio-2-methylpropanoyl)-L-arginine (1 g.) is dissolved in a mixture of water (5 ml.) and concentrated ammonia (5 ml.). After one hour at room temperature the solution is concentrated to 3 ml. in vacuo (no heat) and ion exchange resin AG-50 W is added until the pH of approximately 4. The suspension is applied to a column of the same resin and the Nα-(3-mercapto-2-methylpropanoyl)-L-arginine is eluted with pyridine-acetate buffer pH 6.5. The solvent is removed in vacuo and the residue is freeze dried, yield 0.86 g., m.p. 100°.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][P:14]([CH3:18])(=[O:17])[O:15][CH3:16].[CH2:19]([P:30](Cl)(=[O:34])[O:31][CH2:32][CH3:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][P:14]([CH2:18][P:30]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29])([O:31][CH2:32][CH3:33])=[O:34])(=[O:17])[O:15][CH3:16]
Reactant: COP(C)(=O)OC
Reactant: C=CCCCCCCCCCP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A 2.5 M solution of n-butyllithium in hexane (9.4 mL, 23.5 mmol) was added dropwise with stirring to methylphosphonic acid dimethyl ester (2.65 g, 21.4 mmol) in 100 mL of anhydrous tetrahydrofuran at −78° C. under a nitrogen atmosphere. After 30 minutes, (10-undecenyl)phosphono chloridic acid, ethyl ester (3 g, 10.68 mmol) was added dropwise while stirring was continued. The reaction was stirred at −78° C. for 2 hours then warmed to −50° C. and stirred for an additional 2 hours. Saturated ammonium chloride was then added to neutralize the excess base and the reaction was allowed to warm to ambient temperature. The volatiles were removed by rotary evaporation to give a viscous liquid. This liquid was diluted with ethyl acetate (200 mL) and extracted twice with water (100 mL). The organic layer was collected and dried over sodium sulfate, filtered and concentrated under rotary evaporation to give a viscous liquid. The product was then placed on a high vacuum pump to remove any remaining volatiles (3.07 g, 78% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5](B(O)O)=[CH:4][CH2:3]1.Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[CH3:1][C:2]1([CH3:11])[CH2:7][CH2:6][C:5]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:4][CH2:3]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2ncccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 61 %

Procedure:
A solution of 894 mg (3.78 mmol) of 4,4-dimethyl-cyclohex-1-enylboronic acid and 0.500 g (3.15 mmol) of 2-chloro-3-nitro-pyridine in toluene (20 mL) and EtOH (10 mL) was treated with 12.6 mL (25.2 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 364 mg (0.315 mmol) of Pd(PPh3)4, and heated to 80° C. for 2 h. The mixture was cooled to RT, diluted with EtOAc (50 mL), and washed with saturated aqueous NaHCO3 (1×40 mL) and water (1×40 mL). The aqueous layer was extracted with EtOAc (40 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with CH2Cl2 afforded 446 mg (61%) of the title compound as a yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 8.73 (dd, 1H, J=4.8, 1.6 Hz), 8.02 (dd, 1H, J=8.4, 1.6 Hz), 7.32 (m, 1H), 5.83 (sept, 1H, J=2.0 Hz), 2.50-2.44 (m, 2H), 1.98-1.93 (m, 2H), 1.56 (t, 2H, J=6.0 Hz), 1.00 (s, 6H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1.[Cl-].[NH4+]>C1COCC1>[CH3:15][C:14]([CH3:16])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][O:29]1)[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCCCOC1CCCCO1
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)CCCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (1.78 mL) in dry THF (10 mL) at 0° C. under nitrogen was treated dropwise with n-butyl lithium (2.5M in hexanes, 5.09 mL) to generate a pale yellow solution which was stirred at 0° C. for 30 minutes then cooled to −78° C. and treated dropwise with ethyl isobutyrate (1.55 mL). The solution was stirred at −78° C. for 45 minutes then a solution of 2-(5-bromopentyloxy)tetrahydro-2H-pyran (example 285, step a) (3.20 g) in dry THF (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes then was allowed to warn to room temperature overnight. The reaction mixture was cooled to 0° C. then treated with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate. The aqueous phase was extracted with ethyl acetate (×2) and the combined organic phase was washed with water, saturated aqueous sodium bicarbonate solution and brine then dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0-5% ethyl acetate in cyclohexane to afford the subtitled compound as colourless liquid. Yield 2.22 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[C:16](I)=[N:17][CH:18]=[CH:19][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:22][O:23][C:24](=[O:27])[CH:25]=[CH2:26]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][O:23][C:24](=[O:27])/[CH:25]=[CH:26]/[C:16]1[C:15]([O:14][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C=CC(=O)OC
Reactant: Ic1ncccc1OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ncccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
5.2 g of palladium(II) acetate, 77.8 g of potassium carbonate and 72.5 g of tetrabutylammonium bromide are added to a solution of 70 g of 3-benzyloxy-2-iodopyridine and 39.8 ml of acrylic acid methyl ester in 120 ml of dimethylformamide, and the suspension is stirred under argon atmosphere for 10 hours at 100° C. (bath temperature). The reaction mixture is concentrated by evaporation in a vacuum, the residue is added to water and shaken out with ethyl acetate. The organic phase is washed three times with water and once with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/10-25% ethyl acetate. 48.2 g of 3-(3-benzyloxy-2-pyridyl)-(2E)-2-propenoic acid methyl ester is obtained as oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.[W].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][Br:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc2ccoc12
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: BrCc1cc(Br)cc2ccoc12
Yield: 113.1 %

Procedure:
A mixture of 5-bromo-7-methyl-benzofuran (1.01 g), N-bromosuccinimide (1.04 g) and benzoyl peroxide (58 mg) in carbon tetrachloride (10 ml) was heated at reflux for 4 h under a 250 W tungsten lamp. A further portion of benzoyl peroxide (58 mg) was added and heating and irradiation continued for a total of 9 h. The reaction mixture was allowed to cool, diluted with chloroform (30 ml) and washed with 2N sodium hydroxide (40 ml) and then brine (40 ml). The organic phase was dried, filtered and the filtrate evaporated in vacuo to give the title compound as a brown oil (1.57 g).
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][C:10]1[S:11][C:12]([NH2:15])=[CH:13][N:14]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[CH3:9][C:10]1[S:11][C:12]([NH:15][C:17](=[O:18])[CH3:16])=[CH:13][N:14]=1
Reactant: Cc1ncc(N)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of Et3N (1.4 ml, 10 mmol) and 2-methylthiazol-5-amine hydrochloride (1 g, 6.6 mmol) in DCM (30 mL) was added Ac2O (0.94 mL, 10 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.8 g, yield: 77%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:33][N:34]([CH3:52])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.[OH-].[Na+]>CN(C)C=O.O>[CH3:52][N:34]([CH3:33])[C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)[CH2:40][CH2:39][C:38](=[CH:41][C:42]([NH:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:43])[CH2:37][CH2:36]1
Reactant: NCCCc1ccccc1
Reactant: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C1(c2cccc(F)c2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 29 %

Procedure:
3-phenylpropylamine (768 mg, 5.68 mmol), N-methylmorpholine (1.15 g, 11.36 mmol) and dicyclohexylcarbodiimide (2.34 g, 11.36 mmol) were added to a solution of [4-dimethylamino-4-(3-fluoro-phenyl)-cyclohexylidene]acetic acid (1.5 g, 5.68 mmol) in dry dimethylformamide (35 ml) under argon and the mixture was stirred at RT for 3 d. The urea which had precipitated out was separated off and the filtrate was introduced into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 20 h. The crude product thereby precipitated out as a beige-coloured solid (2.16 g). After chromatography on silica gel G [100 g; EtOAc/MeOH (10:1)], the amide was obtained in a yield of 29% (648.5 mg) with an m.p. of 129-131° C.
Reaction SMILES: CC1C2C(=CC=CC=2)OC(=O)C=1.[C:13]([NH:16][C@H:17]1[C@H:26]([C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[OH:28])[O:25][C:20](O)([C:21](=[O:23])[OH:22])[CH2:19][C@@H:18]1[OH:33])(=[O:15])[CH3:14]>C([O-])(=O)C.[Na+]>[C:13]([NH:16][C@H:17]1[C@@H:26]2[C@@H:27]([C@@H:29]([CH2:31][OH:32])[OH:30])[O:28][C:20]([O:25]2)([C:21](=[O:23])[OH:22])[CH2:19][C@@H:18]1[OH:33])(=[O:15])[CH3:14]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)[O-]
Agent: Cc1cc(=O)oc2ccccc12
Agent: [Na+]
Product: CC(=O)N[C@H]1[C@H]2OC(C(=O)O)(C[C@@H]1O)O[C@@H]2[C@H](O)CO

Procedure:
4-Methylumbelliferyl-N-acetylneuraminic acid (commercially available), 100 mg is incubated with 150 units of sialidase-L in 25 ml of 50 mM sodium acetate buffer, pH 5.5 at 37° C. for 17 hours. The reaction is terminated by the addition of an equal volume of ethanol and the precipitate is removed by centrifugation. The clear supernatant is evaporated to dryness, dissolved in 30 ml of chloroform/methanol (2:1 ν/ν) and subjected to Folch partitioning (Folch, J. Lees, M. and Sloan Stanley, G. H. (1957) J. Biol. Chem. 226, 479-509), by vortexing with 6 ml of water. The 2,7-anhydro-N-acetylneuraminic acid is recovered in the aqueous phase. The organic phase is washed with 8 ml of water. The aqueous phase and the water wash are combined and evaporated to dryness, dissolved in 8 ml of water and applied to a Bio-Gel p-6 column (2.5×90 cm) equilibrated with water. The column is eluted with water at 20 ml per hour wherein 5-ml fractions are collected. Three microliter aliquots of each fraction are analyzed by thin-layer chromatography (solvent:n-butanol/acetic acid/water (2:1:1 ν/ν) and resorcinol spray to locate the product). Fractions containing 2,7-anhydro-N-acetylneuraminic acid are pooled, lyophilized, dissolved in 20 ml of water and applied to a Dowex-1×8 column (formate form, 2×50 cm) equilibrated with water. After washing the column with 800 ml of water to remove the unadsorbed material, the column is eluted with 500 ml of 0.2M formic acid followed by 400 ml of 0.4M formic acid at a flow rate of 40 ml per hour; 10-ml fractions are collected. Under this condition 2,7-anhydro-N-acetylneuraminic acid is eluted by 0.4M formic acid and the eluate is evaporated to dryness to obtain 15 mg of pure 2,7-anhydro-N-acetylneuraminic acid. The above scheme can be proportionally scaled up for large scale preparation of 2,7-anhydro-N-acetylneuraminic acid.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([NH2:13])=[N:7][NH:8]2.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br)#[N:15].O>CS(C)=O>[NH2:13][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[F:3])[N:8]([CH2:19][C:18]2[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])[N:7]=1
Reactant: Nc1n[nH]c2cccc(F)c12
Reactant: N#Cc1cccc(CBr)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(Cn2nc(N)c3c(F)cccc32)c1
Reaction time: 0.5 h

Procedure:
To a suspension of ground potassium hydroxide (0.483 g, 8.60 mmol) in anhydrous dimethyl sulfoxide (15 mL) at room temperature under nitrogen was added a solution of 4-fluoro-1H-indazol-3-amine (for a preparation see Intermediate 36) (0.52 g, 3.44 mmol) in anhydrous dimethyl sulfoxide (10 mL). The resulting deep red solution was treated after 10 minutes with 3-cyanobenzyl bromide (0.843 g, 4.30 mmol) in one portion. The reaction mixture was stirred for 30 min and then poured into water (100 mL), forming a yellow emulsion. This was extracted using chloroform (2×100 mL). The combined organic solutions were washed with water-brine (1:1) (100 mL), passed through a hydrophobic frit and evaporated in-vacuo to yield a red oil (2.263 g). The residue was applied to a 100 g silica SPE cartridge and purified by chromatography on Flashmaster II eluting with a 0-100% ethyl acetate in cyclohexane gradient over 80 min. Fractions 159-173 were combined and the solvent was evaporated in-vacuo to yield a yellow solid the title compound (0.77 g, 84%) LCMS (System B) RT=2.32 min, ES+ve m/z 267 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]CC)=[O:14])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1cnc(N2CCCC2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(N2CCCC2)c(Cl)c1

Procedure:
Ethyl 5-chloro-6-(1-pyrrolidinyl)-3-pyridinecarboxylate (D14) (1.06 g, 4.16 mmol) in ethanol (20 mL) and aqueous sodium hydroxide (2M, 2.08 mL, 4.16 mmol) was heated at 40° C. for 18 h. The reaction mixture was allowed to cool and was neutralised with 2M HCl (aq.). The title compound formed as a white solid and was filtered off and washed with methanol to give the title compound (243 mg, 1.08 mmol) SJ108923-113A3. The filtrate was trapped on an SCX column, eluting with 2M ammonia in methanol to give further title compound as an orange solid (467 mg, 2.07 mmol). δH (methanol-d4, 400 MHz): 8.55 (1H, d), 8.03 (1H, d), 3.76-3.70 (4H, m), 1.96-1.90 (4H, m). MS (ES): C10H11ClN2O2 requires 226, 228; found 227, 229 (MH+).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:2]1.O.[NH2:14][NH2:15].O.CCOC(C)=O>C(O)C>[CH:1]1([C:4]2[NH:15][N:14]=[C:6]([C:7]([F:10])([F:9])[F:8])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C(F)(F)F)C1CC1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1cc(C2CC2)[nH]n1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Intermediate 2 (0.120 g, 0.66 mmol) and hydrazine hydrate (0.04 mL, 0.72 mmol) were dissolved in ethanol (6 mL) and refluxed overnight. Work-up (H2O/AcOEt) after cooling the mixture to RT gave the title compound as a brown solid (0.114 g).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CCCCCC>C(OCC)C>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][Cl:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CO)S1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CCl)S1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-hydroxymethyltetrahydrothiophene (compound No. 1-5, 5.0 g) in anhydrous diethylether (80 ml), triphenylphosphine (9.7 g) and carbon tetrachloride (5.7 g) are added under nitrogen atmosphere and the mixture is stirred for 2 hours at room temperature. n-Hexane (200 ml) is added to the mixture and filtrated. The filtrate is concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give trans-5-tert-butoxycarbonyl-2-chloromethyltetrahydrothiophene.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[ClH:24].O1[CH2:30][CH2:29]OCC1>>[ClH:23].[ClH:24].[N:8]1([CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[CH2:30][CH2:29][CH2:11][CH2:10][CH2:9]1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCCCCCl)cc2C1
Agent: Cl
Product: c1cc2c(cc1OCCCCN1CCCCC1)CNCC2

Procedure:
7-(4-Piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride is prepared from 7-(4-chloro-butoxy)-3,4-dihydro-1-H-isoquinoline-2-carboxylic acid tert-butyl ester (600 mg, 1.5 mmol) and 4N HCl/dioxane (2.5 mL, 10 mmol) base in a manner substantially analogous to Procedure B to give the product (490 mg, 90% yld). MS(ES+)389.3 (M+H)+ free
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[F:27][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(F)c2)O3)nc1

Procedure:
2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 210 mg of 2-(3-fluorophenyl)chroman-6-ol. The product was recrystallised from 2-propanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (d, 1H, J 2.8 Hz), 8.46 (dd, 1H, J 9.0, 2.8 Hz), 7.36 (m, 1H), 7.21-7.15 (m, 2H), 7.03 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.98 (d, 1H, J 8.6 Hz), 6.92 (dd, 1H, J 8.6, 2.7 Hz), 6.90 (d, 1H, J 2.7 Hz), 5.09 (dd, 1H, J 10.3, 2.4 Hz), 3.01 (ddd, 1H, J −16.9, 11.4, 6.0 Hz), 2.82 (ddd, 1H, J −16.9, 5.1, 3.2 Hz), 2.24 (m, 1H), 2.09 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>C(O)(=O)C.O.CCOCC>[F:25][C:26]1[CH:32]=[CH:31][C:29]([N:30]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[CH:11][CH:12]=[C:13]2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:28][CH:27]=1
Reactant: O=C(CCC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2ccc(-c3ccc([N+](=O)[O-])cc3)n2-c2ccc(F)cc2)cc1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
To a slurry of the product from Example 1A (1.5 g, 4.57 mmol) in acetic acid (22.85 mL) was S added 4-fluoroaniline (4.33 ml, 45.7 mmol). The mixture was heated to 70° C. for 24 h. After cooling to rt the mixture was diluted with water and ether and stirred vigorously, filtered and dried to provide 1.67 g (91%) of the title compound.