Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([C@:27]2([NH:34][C:35]([NH2:37])=[S:36])[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2O)[CH:24]=[CH:25][CH:26]=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[C:23]([C@:27]23[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[S:36][C:35]([NH2:37])=[N:34]3)[CH:24]=[CH:25][CH:26]=1
Reactant: NC(=S)N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(c3cccc(Br)c3)CCOC[C@H]2S1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
Diethyl azodicarbonate (13.0 mL) was added dropwise to a solution of triphenylphosphine (7.51 g) in tetrahydrofuran (200 mL) in an ice bath. The mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was cooled to 0° C., and a solution of (±)-[(3R*,4R*)-4-(3-bromophenyl)-3-hydroxytetrahydropyran-4-yl]thiourea (6.33 g) in tetrahydrofuran (44 mL) was added dropwise. The mixture was stirred overnight while gradually warming to room temperature. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain a crude product. The resulting crude product was purified by silica gel column chromatography again to obtain the title compound (3.55 g).
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]([CH2:10][NH2:11])[CH:6]=[CH:7][C:8]=1[F:9].[CH3:12][C:13]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=2)[CH2:21][C@@H:20]1[CH3:35])=[O:18])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:22]3[CH2:23][CH2:24][N:19]([C:17]([O:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:18])[C@@H:20]([CH3:35])[CH2:21]3)[CH:27]=2)[CH:4]=1
Reactant: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 37.3 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (1.68 g, 7 mmol) in dioxane/H2O (10 mL/3.3 mL) was added {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (2.33 g, 7 mmol), K2CO3 (4.83, 35 mmol) and Pd(PPh3)4 (405 mg, 0.35 mmol). The resulting mixture was heated at 150° C. in a pressure vessel for 2 hours, then cooled to rt and diluted with EtOAc (50 mL). The organic layer was collected and the aqueous layer was extracted by EtOAc (30 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by Gilson preparatory HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 90/10, v/v, over 12 min), to give the title compound (1.08 g, 37%). LC/MS: m/z, 414 (M+H), 1.83 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][NH:22]2)=[O:20])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].Cl.C(N(C(C)C)CC)(C)C>C(O)C>[C:9]([C:13]1[O:17][N:16]=[C:15]([NH:18][C:19]([C@@H:21]2[CH2:25][C@@H:24]([OH:26])[CH2:23][N:22]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[O:20])[CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2)no1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2C[C@@H](O)CN2c2ccnc(Cl)n2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-Dichloropyrimidine (33.2 mg, 0.223 mmol) is added to the solution of (2S,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (66 mg, 0.223 mmol) and diisopropylethylamine (0.078 mL, 0.446 mmol) in ethanol (2 mL). The reaction is stirred at room temperature overnight. The reaction is quenched with saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by chromatography on silica eluting with methanol/dichloromethane provides the title compound. ESI m/z 366 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:27](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH3:27][O:19][C:18](=[O:20])[CH:17]([C:16]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:10]2[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (250 mg, 0.67 mmol; example 5.1) in dry DCM (7 mL) was added oxalyl chloride (0.14 ml, 1.67 mmol) drop wise at 0° C. followed by 1 drop DMF and the reaction mixture was stirred at that temperature for 30 min. Ice-bath was removed and stirring was continued for 3.5 h at room temperature. DCM and excess oxalyl chloride was then removed under reduced pressure and MeOH (2 ml) was then added to it at 0° C. After being stirring the reaction mixture at rt for 1 h, TLC shows formation of a new spot. MeOH was removed under vacuo and crude material was passed through a bed of silica gel (SiO2, 100-200 mesh, EtOAc:hexane 30:70) to give the title compound as colorless liquid (250 mg, 95.5%).
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2].[NH2:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([CH3:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1.O.C(OCC)(=O)C>CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>[C:1]([C:3]1[C:8]([NH:11][CH:12]2[CH2:13][C:14]([CH3:21])([CH3:22])[N:15]([CH3:20])[C:16]([CH3:19])([CH3:18])[CH2:17]2)=[CH:7][C:6]([F:10])=[CH:5][N:4]=1)#[N:2]
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Reactant: N#Cc1ncc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1C(C)(C)CC(Nc2cc(F)cnc2C#N)CC1(C)C
Temperature: 115 °C
Yield: 20.5 %

Procedure:
682 mg of 2-cyano-3,5-difluoropyridine, 995 mg of 4-amino-1,2,2,6,6-pentamethylpiperidine and 1.346 mg of potassium carbonate in 10 ml of dimethyl sulphoxide are introduced into a 20 ml microwave tube reactor. The mixture is then heated in the microwave for 1 hour at 115° C. The reaction medium is run into 100 ml of water and 100 ml of ethyl acetate. The aqueous phase is re-extracted twice with 50 ml of ethyl acetate. The combined organic phases are washed with water and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. After purification by flash chromatography on 70 g of silica gel, elution being carried out with a mixture of dichloromethane, methanol and 4N aqueous ammonia (99/1/0.8 by volume), and the first eluted product being recovered, 290 mg of 2-cyano-5-fluoro-3-(1,2,2,6,6-pentamethylpiperidin-4-yl)aminopyridine are thus obtained in the form of an ecru powder, the characteristics of which are the following:
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]([CH3:19])[CH2:16][CH2:17]O)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1>CCOCC>[Br:2][CH2:17][CH2:16][CH:15]([C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)[CH3:19]
Reactant: BrP(Br)Br
Reactant: COc1cc(OC)cc(C(C)CCO)c1
Solvent: CCOCC
Product: COc1cc(OC)cc(C(C)CCBr)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A solution of phosphorous tribromide (5.7 ml., 0.06 mole) in ether (30 ml.) is added to a solution of 3-(3,5-dimethoxyphenyl)-1-butanol (30.0 g., 0.143 mole) in ether (20 ml.) at -5° C. to -10° C. and the reaction mixture stirred at -5° C. to -10° C. for 2.5 hours. It is then warmed to room temperature and stirred for an additional 30 minutes. The mixture is poured over ice (200 g.) and the resulting mixture extracted with ether (3×50 ml.). The combined extracts are washed with 5% sodium hydroxide solution (3×50 ml.), saturated sodium chloride solution (1×50 ml.) and dried (Na2SO4). Removal of the ether and vacuum distillation of the residue affords the title product; 25 g. (55% yield); b.p. 125°-132° C. at 0.4 mm.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C:25]([CH3:37])([CH3:36])[C:26]#[C:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1>CC(O)C.C([O-])(=O)C.[NH2+]1CCCCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][C:27]#[C:26][C:25]([OH:24])([CH3:37])[CH3:36])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:8][CH2:7]1
Reactant: CC(C)(O)C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)(O)C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (400 mg) in 2-propanol (10 mL) were added a solution of 4-[(4-hydroxy-4-methylpent-2-yn-1-yl)amino]-1,3-thiazol-2(5H)-one (365 mg) in 2-propanol (5 mL) and piperidinium acetate (175 mg). The reaction mixture was stirred at 60° C. overnight and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (540 mg).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:34][CH2:35][CH3:36])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:27]([N:17]([C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25])[C:15]1[CH:14]=[CH:13][C:12]2[N:8]([CH2:7][C:6]([OH:37])=[O:5])[C:9]([CH2:34][CH2:35][CH3:36])=[N:10][C:11]=2[CH:16]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccccc3F)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3ccccc3F)ccc2n1CC(=O)O

Procedure:
{5-[Benzyl-(2-fluoro-benzoyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester (0.12 mmol) was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C26H24FN3O3+H: 446, observed: 446.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) and piperidine in DMSO at 23° C. according to the general procedure C. Obtained as a yellow solid (1.173 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[I:30]N1C(=O)CCC1=O>CC#N.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([I:30])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:22])[CH3:23])=[CH:28][CH:29]=1
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cn2c(CO[Si](C)(C)C(C)(C)C)nc(-c3ccccc3)c2I)cc1
Yield: 85 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-tert-butyldimethylsilyloxymethyl-4-phenylimidazole (2.08 g, 5.09 mmol) in MeCN (25 mL) with N-iodosuccinimide (NIS) (1.35 g, 6.00 mmol) at room temperature for 24 hours. Dilute the mixture with Et2O (100 mL), wash with saturated NaHCO3 (25 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.30 g (85% yield). MS (ES+): m/z 535 (M+H)+
Reaction SMILES: Cl.C[O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[N:7]=1)=O.C(O)(C)(C)C.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[Cl:24][C:19]1[CH:18]=[C:17]([N:8]2[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:6]([C:4]([N:44]=[N+:45]=[N-:46])=[O:3])=[N:7]2)[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(-c2cccnc2)n(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(=O)c1cc(-c2cccnc2)n(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3 (100 mg, 0.27 mmol) and t-butyl alcohol (28.4 μL, 0.30 mmol) in DMF (5 mL, anhydrous) was cooled to 0° C. Diphenylphosphoryl azide (64 μL, 0.30 mmol) was added to the solution. Triethylamine (103 μL, 0.60 mmol) was then added over 10 min. The solution was stirred 1 h at 0° C. and allowed to warm to room temperature and stir 16 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with H2O, dried (brine and MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography by eluting with hexane-EtOAc (1:1). Collected 4 (86 mg, 90%) as a yellow crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:21]=O)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>O.C(#N)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:21][C:15]2[C:16]([O:19][CH3:20])=[N:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: COc1ncc(F)cc1C=O
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NCc2cc(F)cnc2OC)nc1
Yield: 83.3 %

Procedure:
In a round bottom flask, 6-amino-nicotinic acid methyl ester (90, 0.678 g, 4.46 mmol) was combined with 5-fluoro-2-methoxy-pyridine-3-carbaldehyde (37, 0.532 g, 3.43 mmol), 10.6 mL of acetonitrile, trifluoroacetic acid (1.32 mL, 17.1 mmol) and triethylsilane (3.29 mL, 20.6 mol). The reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (91, 832 mg). MS (ESI) [M+H+]+=292.4.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[OH-].[Li+]>CS(C)=O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12])([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1c(N)sc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2ccccc12
Temperature: 50 °C
Yield: 83 %

Procedure:
By using a method similar to the method of Example 490, combine 2-amino-benzo[b]thiophene-3-carbonitrile (3.56 g, 20.5 mmol), 2-fluoro-nitrobenzene (2.88 g, 20.5 mmol) and Lithium hydroxide (0.96 g, 41.0 mmol) ) in 50 mL of DMSO and heat to 50 ° C., after over night heating to give 5.0 g, yield 83%. Mass spectrum: ES(+) (m/e): 296.0 ((M+1); 1H NMR (400 MHz, DMSO-d6) ppm: 10.27 (s, 1H), 8.13 (dd, 1H, J=1.7 Hz, J=8.3 Hz), 7.91–7.89 (m, 1H), 7.76–7.72 (m, 1H), 7.64–7.57 (m, 2 H), 7.48–7.44 (m, 1H), 7.36–7.32 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:21]=[C:22]1[C:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][CH2:24][N:23]1[CH2:39][C:40](O)=[O:41].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:40](=[O:41])[CH2:39][N:23]3[CH2:24][CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]3=[O:21])[CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccccc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-((4-fluorophenyl)(phenyl)methyl)piperazine (0.27 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40-7.49 (m, 4H), 7.25-7.35 (m, 10H), 7.17-7.24 (m, 3H), 7.08-7.17 (m, 2H), 4.36 (s, 1H), 4.14-4.15 (br s, 2H), 3.40-3.48 (m, 4H), 3.35 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.22-2.28 (m, 4H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2O)[N:11]=1)(=[O:8])[CH3:7].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:6]([NH:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[Cl:3])[N:11]=1)(=[O:8])[CH3:7]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc2c(O)ccnc2n1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(=O)Nc1ccc2c(Cl)ccnc2n1
Yield: 18 %

Procedure:
Phosphorous oxychloride (6.0 ml) was added to a stirred mixture of 2-acetamido-5-hydroxy-1,8-naphthyridine (2.4 g, 11.8 mmol) and N,N-dimethylaniline (6.0 ml) in toluene (100 ml). The mixture was then heated at reflux for 1 hour. The mixture was allowed to cool, the tolulene was removed by evaporation and the residue was partitioned between methylene chloride and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent was removed by evaporation to give 2-acetamido-5-chloro-1,8-naphthyridine (470 mg, 18%) as a brown solid.
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][CH2:5][O:6][CH:7]=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH2:3][CH2:4][CH2:5][O:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: BrC1=COCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Clc1ccc(C2=COCCC2)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
A mixture of 5-bromo-3,4-dihydro-2H-pyran (1.0 g, 6.13 mmol), (4-chlorophenyl)boronic acid (1.05 g, 6.74 mmol), potassium carbonate (2.5 g, 18.4 mmol), Pd(dppf)C12 (449 mg, 0.613 mmol), and ethanol/water (2/2 mL) in toluene (10 mL) was stirred at 100° C. for 12 hours. The mixture was filtered, and the filtrate was evaporated and purified by silica gel chromatography to give the title compound (700 mg, 58.8%) as orange solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.25 (d, 2 H), 7.20 (d, 2 H) 6.90 (s, 1 H), 4.03 (t, 2 H), 2.37 (t, 2 H), 2.02 (m, 2 H)
Reaction SMILES: ClC(Cl)(Cl)[CH:3](O)[OH:4].S([O-])([O-])(=O)=O.[Na+].[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([NH2:24])[C:18]=2[O:17][CH2:16]1.S(O)(O)(=O)=O.NO.Cl>O>[O:17]1[C:18]2[C:23]3[NH:24][C:3](=[O:4])[C:22]=3[CH:21]=[CH:20][C:19]=2[O:15][CH2:16]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Nc1cccc2c1OCO2
Agent: Cl
Agent: NO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Nc2c1ccc1c2OCO1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
To a slurry of chloral hydrate (1.39 g, 8.4 mmol) and sodium sulfate (6.91 g, 48.7 mmol) in water (23.1 mL) was added benzo[d][1,3]dioxol-4-amine (1.0 g, 7.3 mmol), hydroxylamine sulfate (6.24 g, 38 mmol) and diluted hydrochloric acid (1.2 N, 7.7 mL). After stirring at 60° C. for 1.5 hours, the reaction mixture was kept at 25° C. overnight. The brown solid was collected by filtration and washed with water. After drying under vacuum, the solid was taken up in methane sulfonic acid and the solution was heated at 45° C. for 30 minutes. The mixture was cooled to 0° C. and then poured into ice (200 g). A dark red solid was precipitated and collected by filtration, dried to afford the product (635 mg, yield 53%). 1H NMR (400 MHz, CDCl3) δ ppm 7.68 (br s, 1H), 7.35-7.37 (d, 1H, J=8.0 Hz), 6.59-6.61 (d, 1H, J=8.0 Hz), 6.13 (s, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:23]1[CH:27]=[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[O:25][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N+]=[N-]>O1CCCC1>[NH2:7][CH:10]([C:23]1[CH:27]=[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[O:25][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reaction time: 1 h

Procedure:
Lithium aluminium hydride (a 1M solution in tetrahydrofuran; 1.1 ml, 1.1 mmol) was added dropwise to a solution of 3-(1-azidotridecyl)-5-trimethylsilylfuran (334 mg, 0.92 mmol) in tetrahydrofuran at room temperature. After one hour at room temperature, the excess hydride was destroyed by adding acetone slowly to the mixture with cooling. Sodium sulfate (ca. 0.5 g) was added and the mixture was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% methanol/dichloromethane containing 0.2% triethylamine. Fractions with Rf of about 0.18 on evaporation gave the title amine as a pale yellow oil.