Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:45]1[CH2:48][CH:47]([C:49]([N:51]2[CH2:57][CH2:56][CH2:55][N:54]([CH:58]3[CH2:61][CH2:60][CH2:59]3)[CH2:53][CH2:52]2)=[O:50])[CH2:46]1>C(Cl)Cl>[CH:58]1([N:54]2[CH2:55][CH2:56][CH2:57][N:51]([C:49]([CH:47]3[CH2:46][N:45]([C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=4)=[O:10])[CH2:48]3)=[O:50])[CH2:52][CH2:53]2)[CH2:61][CH2:60][CH2:59]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: Cc1ncc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ncc(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 3 h
Yield: 28.6 %

Procedure:
To a stirred solution of 2-methylpyrimidine-5-carboxylic acid (23 mg, 0.17 mmol) in DCM (3 ml) was added HOBt (23 mg, 0.17 mmol) and HBTU (64 mg, 0.17 mmol). After 3 hours, a solution of 1-(Azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (48 mg, 0.17 mmol), in DCM (1 ml) was added and the yellow suspension gradually dissolved to give a yellow solution. The reaction mixture was quenched with saturated NaHCO3 (1 ml) and the aqueous layer extracted with DCM (3×5 ml). The combined organic layers were dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 99:1 to 95:5 gradient of DCM/2M NH3 in MeOH) gave the title compound (17.4 mg, 29% yield) as pale yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:23][OH:24])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NO
Reactant: N#Cc1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(C(CCC(=O)O)=NO)cc2)cc1
Reaction time: 60 h
Yield: 49.6 %

Procedure:
A stirred suspension of 4-(4′-cyano-biphenyl-4-yl)-4-oxo-butyric acid (0.7908 g, 0.002831 mol), hydroxylamine hydrochloride (0.2038 g, 0.00293 mol), sodium carbonate (0.3158 g, 0.00298 mol) in absolute ethanol (17 mL) was refluxed under nitrogen for 12 hours and allowed to cool. The mixture was allowed to stand for 2.5 days for convenience. Volatiles were rotary evaporated, and the residue was partitioned between dichloromethane-tetrahydrofuran (50/50 v/v) and 0.05 M aqueous hydrochloric acid (60 mL). The aqueous layer was extracted with additional organics. The extracts were combined, dried (Na2SO4) and rotary evaporated. The residue was dissolved/suspended in dichloromethane and chromatographed on silica gel (165 g, 230-400 mesh), eluting with dichloromethane-methanol (25:1, 30×125 mL; 15:1, 5×125 mL) to give 0.413 g of 4-(4′-cyano-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 157-159° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=3)[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)(=O)=O)=CC=1.[N-:44]=[N+]=[N-].[Na+].O>CS(C)=O>[Cl:43][C:38]1[CH:37]=[C:36]([C:13]2([CH2:12][NH2:44])[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[O:32][C:31]([CH3:33])=[N:30][CH:29]=5)=[C:24]([O:34][CH3:35])[CH:23]=4)=[N:20][N:21]=[C:14]23)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(-c2nnc3n2CCCC3(COS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(-c2nnc3n2CCCC3(CN)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Temperature: 100 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of {8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl}methyl 4-methylbenzenesulfonate (150 mg) and sodium azide (45.8 mg) in DMSO (2 mL) was stirred at 100° C. for 2 days. Water was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was dissolved in THF (2 mL)/water (2 mL), diphenylphosphino-polystyrene (1.99 mmol/g, 236 mg) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was filtered, and the solvent in the filtrate was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (55.5 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][C:15]=3F)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:22])[CH2:3]1.Cl.Cl.[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:35][NH2:36])=[C:29]2[CH2:28][CH2:27]1>>[NH:26]1[C:30]2=[N:31][CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([NH:12][C:8]3[CH:7]=[C:6]4[C:11]([C:2]([CH3:23])([CH3:1])[CH2:3][C:4](=[O:22])[NH:5]4)=[CH:10][CH:9]=3)=[O:21])=[C:29]2[CH2:28][CH2:27]1
Reactant: NCc1ccnc2c1CCN2
Reactant: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3F)ccc21
Agent: Cl
Product: CC1(C)CC(=O)Nc2cc(NC(=O)c3cccnc3NCc3ccnc4c3CCN4)ccc21

Procedure:
The titled compound was prepared from N-(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2-fluoro-nicotinamide and C-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 437 (M+H). Calc'd. for C25H26N6O2—442.52.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31](Cl)(=O)C.C[Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[C:29]([CH3:31])[CH:30]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344 mmol) was dissolved in THF (3.5 mL) and cooled to 0° C. Acetyl chloride (0.0256 ml, 0.361 mmol) was added and the reaction was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412 mmol) was added. The reaction was stirred 1 hr. at 0° C. and then warmed to RT and quenched with saturated ammonium chloride and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium hydroxide, water, brine, and dried over sodium sulfate. The crude product was dissolved in isopropylacetate (4 mL) and heated to 50° C. before DDQ (0.117 g, 0.515 mmol) was added. After 30 minutes the reaction was cooled and diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, once with water, brine, and dried over sodium sulfate. The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and concentrated to afford the title compound, MS m/z: 451.3 (100%, M+1)).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(N)cccc1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Methyl 2,6-dinitrobenzoate (15.0 gm.) is suspended in methanol (500 ml.) and 5% palladium on charcoal (1.5 gm.) added. Reduction is carried out on a Parr apparatus for 2 hours. The solution is filtered with suction and the catalyst washed with a few ml. of methanol. Removal of the methanol gives a brown crystalline product. Extraction with chloroform (50 ml.) and treatment with Darco gives the product (10.9 gm. 96% yield, m.p. 78°-79.5°). The thin layer chromatogram (Silica gel, 3% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: Cl[CH:2]([C:13](=O)[CH2:14][CH2:15][CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[C:18]([NH2:21])(=[S:20])[CH3:19]>C(OCC)(=O)C>[CH3:19][C:18]1[S:20][C:2]([CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[C:13]([CH2:14][CH2:15][CH3:16])[N:21]=1
Reactant: CCCC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=S
Solvent: CCOC(C)=O
Product: CCCc1nc(C)sc1Cc1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 5.9 of 2-chloro-1-(4-nitrophenyl)hexan-3-one and 1.7 g of thioacetamide is heated at 90°-100° C. for 6 hours and then cooled and taken up with ethyl acetate. The precipitate formed is filtered off and washed with ethyl acetate and then with ether to give 5.6 g of 2-methyl-4-propyl-5-(4-nitrobenzyl)thiazole in the form of crystals melting at 124° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:16][CH3:17])=[N:8][N:9]3[C:14]([I:15])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([S:16][CH3:17])=[N:8][N:9]3[C:14]([I:15])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:24][CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)[CH2:2][CH2:3]1
Reactant: O=CC1CCOCC1
Reactant: CSc1nn2c(I)cccc2c1NCC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (70 mg) in tetrahydrofuran (2.5 mL) was added tetrahydropyran-4-carbaldehyde (56 mg) at room temperature, and then sodium triacetoxyborohydride (103 mg) was gradually added. After 1 hour, saturated aqueous sodium bicarbonate was added, extraction was performed with ethyl acetate, the extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford a crude product of the title compound (50 mg) as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:27])=[O:26]
Reactant: CCCCCCCC(=O)NCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCCCOS(C)(=O)=O
Yield: 81.6 %

Procedure:
To a solution of 2.00 g (7.77 mmol) of N-(5-hydroxypentyl)caprylamide and 1.30 ml (9.32 mmol) of triethylamine in 50 ml of methylene chloride was added 0.72 ml (9.32 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 1.95 g of the desired compound (74.8%, colorless powder), mp: 67.0-68.0° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:14])[CH2:5][C:6](Br)([N+]([O-])=O)[C:7]=1[O:8][CH3:9].[N:15]#N>C(O)C.[Pd]>[F:14][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[CH:2][C:3]=1[NH2:15]
Reactant: COC1=C(Br)C=C(F)CC1(Br)[N+](=O)[O-]
Reactant: N#N
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A 2.0 L pressure reactor was charged with 10% Pd/C (50% wet paste, 10 g). A solution of 1,5-dibromo-3-fluoro-6-methoxy-5-nitrobenzene (50 g, 0.152 mol) in ethanol (absolute grade, 1.5 L) was added to the catalyst under N2. The stirred reaction mixture was subjected to three cycles of vacuum followed by N2 purge. The reaction mixture was evacuated prior to the introduction of H2 at a pressure of 4 bars. The reaction mixture was evacuated and H2 was introduced until a pressure of 7 bars was reached. The reaction mixture was stirred at 25° C. for 48 hours, with periodic injections of H2 to maintain the internal pressure at 7 bars (note that after 24 hours, the catalyst was replaced). After the reaction had reached completion, the catalyst was removed by filtration through 2 glass microfibre pads under an atmosphere of N2 and the filtrate was concentrated to dryness under reduced pressure at 45° C. The resulting dark orange solid was dissolved in water (500 mL) and the pH of the resulting solution adjusted to >12 using aqueous NaOH (1N, 400 mL). The resulting brown suspension was extracted with tert-butylmethylether (2×1 L). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered and concentrated in vacuo at 40° C. to afford 2-Fluoro-5-methoxyaniline (18.0 g, 84%) as a brown solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)N1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCN(C(=O)OCc2ccccc2)N1CCc1ccccc1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
Sodium hydride (562 mg, 14.1 mmol, 60% mineral oil dispersion) is added to a solution of 1-(benzyloxycarbonyl)pyrazolidin-3-one (2.81 g, 12.8 mmol, prepared similarly to that described in J. Org. Chem. 1990, 55, 6037) and DMF (37 mL) at 0° C. The solution is stirred for 30 minutes and then (2-bromoethyl)benzene (1.90 mL, 13.9 mmol) is added. The solution is stirred at 0° C. for 1 hour and 16 hours at room temperature. Aqueous workup (EtOAc, brine, MgSO4) and purification by flash chromatography (2:1→1:1 hexane:EtOAc) gives 1.58 g (38%) of the title compound as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[CH:13][C:12]([C:15]([NH:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.Cl.[NH:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]1>C(#N)C>[CH2:18]([NH:17][C:15]([C:12]1[CH:11]=[N:10][C:9]([N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]2)=[N:14][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCNC(=O)c1cnc(Cl)nc1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNC(=O)c1cnc(N2CCC[C@H](O)C2)nc1
Temperature: 80 °C
Yield: 73.9 %

Procedure:
Triethylamine (1.5 mL, 11 mmol) and 2-chloro-N-ethylpyrimidine-5-carboxamide (830 mg, 4.47 mmol) were added sequentially to a solution of (S)-piperidin-3-ol hydrochloride (677 mg, 4.92 mmol) in acetonitrile (25 mL) at 20-25° C. The reaction mixture was heated to 80° C. for 16 hours. The mixture was then cooled to 20-25° C. and was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (25 mL) and washed with saturated NH4Cl (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated to provide (S)—N-ethyl-2-(3-hydroxypiperidin-1-yl)pyrimidine-5-carboxamide (827 mg, 73%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][N:18]=1.O[CH2:27][C:28]1([CH2:32][CH2:33][CH3:34])[CH2:31][O:30][CH2:29]1>CN(C)C=O>[Cl:16][C:17]1[N:18]=[CH:19][C:20]([C:21]([O:23][CH2:27][C:28]2([CH2:32][CH2:33][CH3:34])[CH2:31][O:30][CH2:29]2)=[O:22])=[CH:24][CH:25]=1
Reactant: CCCC1(CO)COC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCC1(COC(=O)c2ccc(Cl)nc2)COC1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of dicyclohexylcarbodiimide (2.0 gm.) in dry dimethylformamide (5 ml.) was added to a stirred solution of 6-chloronicotinic acid and 3 -hydroxymethyl-3-n-propyloxetane in dry dimethylformamide (15 ml.) at room temperature. The reaction mixture was stirred at room temperature for 60 hours. The mixture was filtered and the solid was washed with diethyl ether (50 ml.). The filtrates were washed with water and then with 5% aqueous sodium carbonate solution. The etheral solution was washed with brine and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The residue was purified by chromatography on silica, eluting with 1% triethylamine:chloroform. (3-n-propyl-oxetan-3-yl)methyl 6-chloro-3-pyridinecarboxylate was obtained as an oil, which solidified on standing (289 mg.).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O-:15].[Na+].O>C1COCC1>[F:13][C:9]1[C:10]([CH3:12])=[N:11][C:2]([O:15][CH3:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c(C)nc1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(F)c(C)nc1OC
Temperature: 60 °C
Reaction time: 6 h
Yield: 32 %

Procedure:
To a stirred solution of methyl 2-chloro-5-fluoro-6-methylnicotinate (18) (0.8 g, 3.92 mmol,) in THF (35 mL) was added sodium methanolate (0.42 g, 7.85 mmol) at 0° C. The mixture was stirred at 60° C. for 6 hours and cooled to room temperature. Then the mixture was poured into water and extracted with dichloromethane (2×50 mL). The combined organic layer was washed with water, brine and solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexane to give methyl 5-fluoro-2-methoxy-6-methylnicotinate (19) (250 mg, 32%) as a white solid.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[S:4][CH2:3]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(#N)C>O>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]2[C@H:11]([OH:12])[C@H:2]([CH2:3][N:14]3[CH:18]=[CH:17][N:16]=[CH:15]3)[S:4][C:5]=2[CH:6]=1
Reactant: c1c[nH]cn1
Reactant: OC1c2ccc(Cl)cc2SCC1Br
Solvent: O
Solvent: CC#N
Product: O[C@H]1c2ccc(Cl)cc2S[C@H]1Cn1ccnc1

Procedure:
Add 3-bromo-7-chlorothiochroman-4-ol (5.27 g., 18.8 mmole) and imidazole (12.8 g., 188 mmole) to acetonitrile (100 mL.), and reflux for 4 hours. Pour the reaction mixture into water (500 mL.), and extract with chloroform (500 mL.). Wash the organic layer with water (500 mL.), dry it over anhydrous magnesium sulfate, filter and evaporate in vacuo. Triturate the residue with anhydrous ether, filter and recrystallize from acetonitrile to give (±)-cis-6-chloro-2,3-dihydro-3-hydroxy-2-(1H-1-imidazolylmethyl)benzo[b]thiophene, m.p. 164°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]([O:20][CH2:21][CH:22]1[CH2:24][O:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: c1ccc(COCC2CO2)cc1
Product: COc1ccc(CNCC(O)COCc2ccccc2)c(OC)c1

Procedure:
Starting materials: 2,4-dimethoxy-benzylamine and 2-[(benzyloxy)methyl]oxirane
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[CH:26]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A microwave vial was charged with tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (300 mg, 0.773 mmol), trimethylsilylacetylene (0.22 mL, 1.54 mmol), NEt3 (3.0 mL), DMF (1.5 mL), CuI (15 mg, 0.080 mmol), and PdCl2(PPh3)2 (27 mg, 0.039 mmol). The vial was capped and heated in the microwave at 100° C. for 1 h. After removing the NEt3 in vacuo, the residue was extracted with EtOAc (15 mL). The organic layer was then washed with NaHCO3 (sat.) (5 mL), H2O (5 mL), brine (5 mL) and then dried over MgSO4. The solvent was removed and then the material was dissolved into MeOH (4 mL) and THF (2 mL). K2CO3 (1.0 mL of a 1M solution) was added and the reaction stirred for 3 h. The solvent was removed and the residue extracted with EtOAc (15 mL). The organic layer was washed with brine (5 mL) and then dried over MgSO4. The solvent was removed and the product dried under high vacuum to give the title compound as a brown solid (212 mg, 96%); MS ESI 287.0 [M+H]+, calcd for [C17H22N2O2+H]+ 287.18.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]([CH2:25][CH2:26]F)([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)[Br:29]>ClCCl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:23]4[C:18]([CH2:25][CH2:26][Br:29])([CH2:19][CH2:20][C:21](=[O:24])[CH:22]=4)[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCF)CC1
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C=C2c3ccc4nn(Cc5ccccc5)cc4c3CC2(CCBr)CC1
Temperature: -5 °C

Procedure:
A solution of 2-benzyl-9a-(2-fluoroethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H)-one (3.2 g, 8.88 mmol) in 90 mL of dichloromethane was cooled to −65° C. and a 1M solution of boron tribromide in dichloromethane (27 mL, 27 mmol) was added dropwise during 15 minutes. The reaction mixture was allowed to warm to −5° C. during 30 minutes and was then partitioned between EtOAc and 5% aqueous NaHCO3. The organic phase contained some solid material which was dissolved by addition of dichloromethane and methanol. The organic layer was washed with water and brine and dried over MgSO4. Evaporation under vacuum gave 2-benzyl-9a-(2-bromoethyl)-8,9,9a,10-tetrahydroindeno[2,1-e]indazol-7(2H)-one as an orange solid which was dissolved in THF (175 mL). The resulting solution was cooled to −65° C. and a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (22 mL, 11 mmol) was added dropwise during 15 minutes. The reaction mixture was allowed to warm to −5° C. during 25 minutes at which point HPLC analysis of an aliquot showed a small amount of unreacted starting material. An additional portion of 0.5M potassium bis(trimethylsilyl)amide in toluene (1 mL, 0.5 mmol) was added and the cooling bath was removed. After 15 minutes more, the reaction was quenched by the addition of 1N HCl (30 mL). The reaction mixture was partitioned between EtOAc and water and the organic phase was washed with 5% aqueous NaHCO3 and brine dried over MgSO4. Concentration of the organic solution under vacuum gave a precipitated solid which was isolated by filtration to give 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one. The filtrate was concentrated under vacuum and the residue chromatographed on silica gel (elution with 2:3 to 1:1 EtOAc/hexanes) to yield additional 2-benzyl-2,9,10,11-tetrahydro-8,10a-methanoazuleno[2,1-e]indazol-7(8H)-one as a solid.