Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH2:16].[Na].FC(F)(F)C([O-])=O>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:14][CH2:13][C:5]2[N:6]([CH2:16][CH2:15][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1ccncc1
Reactant: CN1CCc2[nH]c3ccccc3c2C1
Agent: [Cu+2]
Agent: O=C([O-])C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CN1CCc2c(c3ccccc3n2CCc2ccncc2)C1
Yield: 19.2 %

Procedure:
The title compound was prepared according to General Method 3. 2,3,4,5-Tetrahydro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (See Example 3) (200 mg, 1.07 mmol), 4-vinylpyridine (0.26 mL, 2.41 mmol), sodium (5 mg, 0.21 g atom) and CuSO4 (5 mg, catalytic) in ethanol (4 mL) at 120° C. for 16 h (overnight) to obtain 60 mg of 2,3,4,5-tetrahydro-2-methyl-5-(2-(pyridin-4-yl)ethyl)-1H-pyrido[4,3-b]indole as trifluoroacetate salt after purification on reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:10]2)=CC=1.[Cl:23][C:24]1[C:25]([NH:39][C:40](=O)[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2>O1CCCC1>[Cl:23][C:24]1[C:25]([NH:39][C:40](=[S:10])[CH2:41][O:42][CH3:43])=[C:26]2[C:31](=[CH:32][C:33]=1[CH3:34])[N:30]=[C:29]([O:35][CH3:36])[C:28]([O:37][CH3:38])=[N:27]2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCC(=O)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Solvent: C1CCOC1
Product: COCC(=S)Nc1c(Cl)c(C)cc2nc(OC)c(OC)nc12
Reaction time: 18 h
Yield: 145 %

Procedure:
2,4-bis(4-Methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent) (4.47 g, 11.06 mmol) was added to 6-chloro-2,3-dimethoxy-5-methoxyacetamido-7-methylquinoxaline (6 g, 18.43 mmol) in tetrahydrofuran (120 mL) and the mixture stirred for 18 hours, then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:dichloromethane (1:1 changing to 1:4 changing to 0:1, by volume) to give 6-chloro-2,3-dimethoxy-5-methoxythioacetamido-7-methylquinoxaline (5.48 g, 87%) as a yellow foam, mp 174-176° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:24]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([CH3:18])([CH3:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:24])=[O:5]
Reactant: CO
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Yield: 92 %

Procedure:
A solution of 49.8 g (0.199 mol) of 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoic acid in 200 ml of methanol was heated to 50° C. and then treated dropwise with about 80 g of sulfuric acid at a rate to maintain the reaction under reflux. The reaction mixture was heated under reflux for an additional 11 hours, then cooled and partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and taken to dryness to give 48.6 g (92%) of methyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>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>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3F)nc2)cs1
Temperature: 150 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.43 mmol, 100 mg), 2-fluorophenylboronic acid (0.47 mmol, 66 mg), dichlorobis(triphenylphosphine)palladium(II) (0.03 mmol, 18 mg), and potassium carbonate (1.72 mmol, 238 mg) were added to deoxygenated DME:water (1:1, 3 mL) at room temperature. The reaction was heated for 5 min at 150° C. via microwave irradiation, then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 10 to 40% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.13 (s, 1H), 8.69 (d, 1H), 8.30 (d, 1H), 7.98 (s, 1H), 7.84 (dd, 1H), 7.70 (m, 1H), 7.42-7.53 (m, 2H), 2.83 (s, 3H). MS (ESI) 295.13 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][OH:44])([CH3:37])([CH3:36])[CH3:35].[Cl:46][C:47]1[CH:56]=[CH:55][CH:54]=[C:53]2[C:48]=1[C:49](O)=[CH:50][C:51](=[O:57])[O:52]2>C1COCC1>[C:34]([O:38][C:39](=[O:45])[NH:40][CH2:41][CH2:42][CH2:43][O:44][C:49]1[C:48]2[C:47]([Cl:46])=[CH:56][CH:55]=[CH:54][C:53]=2[O:52][C:51](=[O:57])[CH:50]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: O=c1cc(O)c2c(Cl)cccc2o1
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCOc1cc(=O)oc2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 20 %

Procedure:
A solution of triphenylphosphine (0.438 g, 1.67 mmol) in 10 mL of THF is cooled to −78° C. and DIAD (0.430 g) is added in one portion. (3-Hydroxy-propyl)-carbamic acid tert-butyl ester (560 mg, 1.3 eq) in 1 mL of THF is added and the solution is allowed to warm to room temperature over the course of 1 hr. The yellow solution is treated with 5-chloro-4-hydroxycoumarin (0.300 g, 1.5 mmol) and is stirred at ambient temperature for 3.5 hrs. The solvent is removed under reduced pressure and the crude product is purified using an ISCO 4 g SiO2 column eluting with ether/heptane gradient to afford the title compound (0.106 g, 20%). 1H NMR (CDCl3, 300 MHz) δ 7.27 (3H, m), 5.71 (1H, s), 4.73 (1H, brs), 4.17 (2H, t, J=5.75 Hz), 3.41 (2H, q, J=6.5 Hz), 2.13 (2H, m), 1.43 (9H, s); MS (ESI, Pos.) calcd for C17H20ClNO5 m/z [M+H+Na]=376.1, found 376.1.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=1[F:33])[CH2:9][C:10]([NH:12][NH:13][C:14]1[N:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:18]2[CH2:17][CH2:16][N:15]=1)=O)(C)(C)C.[C:35](O)(=O)C>>[CH3:23][C:21]1[N:22]=[C:18]2[N:19]([C:14]3[N:15]([C:10]([CH2:9][C@H:8]([NH:7][C:6](=[O:5])[CH3:35])[CH2:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=4[F:33])=[N:12][N:13]=3)[CH2:16][CH2:17]2)[N:20]=1
Reactant: CC(=O)O
Reactant: Cc1nc2n(n1)C(NNC(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)=NCC2
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1nc(C)nn1-2

Procedure:
The crude residue from Step A was dissolved in 5 mL of glacial acetic acid, and the resulting solution was stirred at reflux for 60 h. The cooled solution was concentrated, and the residue was partitioned between 1:1 ethyl acetate:tetrahydrofuran and saturated sodium carbonate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. Purification of the residue by preparative thin-layer chromatography on silica gel (three successive developments in 95:5, 92.5:7.5, and 90:10 dichloromethane:methanol) afforded the title compound as a stiff foam. LC-MS 406 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[Cl:15].[C:23]([O:27][C:28]([NH:30][CH2:31][CH2:32]Br)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C.O>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[Cl:15])[NH:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:32][CH2:31][NH:30][C:28](=[O:29])[O:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1
Reactant: Clc1ccc(NC2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCBr
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCN1CCC(Nc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 16 h

Procedure:
The product from step (ii) above (2.0 g), N-tert-butoxycarbonyl-2-bromoethanamine (1.0 g) and N,N-di-isopropylethylamine (3.7 ml) were dissolved in DMF (25 ml) and stirred for 16 hours. Water and ethyl acetate were added, the organic phase separated, dried and evaporated to give a gum. Purification by chromatography (dichloromethane:methanol, 95:5) gave the sub-titled product as a solid (1.25 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=O.Cl.[CH3:13][O:14][NH2:15]>N1C=CC=CC=1>[CH3:13][O:14][N:15]=[C:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromoindan-1-one (5.08 g, 24.1 mmol) was added to a mixture of methoxyamine hydrochloride (2.21 g, 26.5 mmol) in pyridine (40 mL) under nitrogen atmosphere and stirred overnight at ambient temperature. The reaction mixture was concentrated, added ethyl acetate (200 mL), washed with 3N hydrochloric acid (200 mL), dried with brine and anhydrous sodium sulfate, and concentrated. Obtained 4-bromoindan-1-one O-methyloxime (5.66 g, 98%) as an orange liquid. MS (DCI/NH3) m/z: 239.94 [M+H]+. 1H NMR (DMSO-d6) □: 2.83 (m, 2H), 2.96 (m, 2H), 3.91 (s, 3H), 7.25 (t, 1H), 7.56 (d, 1H), 7.60 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:19]([NH:23][C:24]1[C:25]([NH2:48])=[C:26]([O:39][CH2:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[CH:27]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])[CH:29]=1)[CH2:20][CH2:21][CH3:22]>C(O)C>[CH2:19]([N:23]1[C:24]2[CH:29]=[C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])[CH:27]=[C:26]([O:39][CH2:40][CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])[C:25]=2[N:48]=[C:15]1[C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1)[CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccc(OCCc2ccc(Cl)cc2)cc1
Reactant: CCCCNc1cc(OCCCN(CC)CC)cc(OCCCN(CC)CC)c1N
Solvent: CCO
Product: CCCCn1c(-c2ccc(OCCc3ccc(Cl)cc3)cc2)nc2c(OCCCN(CC)CC)cc(OCCCN(CC)CC)cc21
Yield: 31.9 %

Procedure:
This compound was prepared according to General Procedure K by refluxing a mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (300 mg) and N1-Butyl-3,5-bis-(3-diethylamino-propoxy)-benzene-1,2-diamine (synthesized via General Procedures J1 and J2 and I) (200 mg) in ethanol overnight. Ethanol was removed in vacuo and the residue was purified by silica gel chromatography using 5% MeOH in DCM to give pure (3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopropoxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (100 mg).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCNCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of N-benzylethylenediamine (6.0 g, 40 mmol) in toluene (50 ml) at 0° C. was added 1,1′-carbonylbis-1H-imidazole (7.8 g, 48 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was washed with water, 5% aqueous citric acid solution and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallized with warm ethyl acetate and filtered off to give 1-benzylimidazolidin-2-one (3.47 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2([O:39]CC3C=CC=CC=3)[CH:17]=[CH:16][C:15]([N:18]([C:25]3[CH:30]=[CH:29][C:28]([O:31]CC4C=CC=CC=4)=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2([OH:39])[CH:13]=[CH:14][C:15]([N:18]([C:25]3[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:16][CH2:17]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N=NC2(OCc3ccccc3)C=CC(N(c3ccccc3)c3ccc(OCc4ccccc4)cc3)=CC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(N=NC2(O)C=CC(N(c3ccccc3)c3ccc(O)cc3)=CC2)cc1
Yield: 60 %

Procedure:
To a 500 mL flask equipped with a nitrogen inlet and a magnetic stir was added 20 g (0.033) dibenzyl ether 2 from Example 1B and 330 mL (0.3M) trifluoroacetic acid (Aldrich). The dark blue mixture was allowed to stir at room temperature for 48 hours after which all of 2 had been consumed as measured by LC in addition to one minor impurity (monobenzyl ether). The reaction was quenched with 1 L ice water and the bisphenol was extracted into 300 mL Et2O. The organic layer was washed 2×100 mL H2O 5×100 mL aq. sodium bicarbonate (sat.) and 2×100 mL H2O dried over MgSO4, filtered and reduced in vacuo giving ca. 20 g crude 3 as a dark red powder (ca. 60 percent by LC). All attempts at recrystallization failed and the two components were separated by high pressure flash chromatography (Biotage) on silica with CH3 CN/CH2Cl2 (20/80 percent) TLC ΔRf =0.119) giving 3.2 g of BHPD as a red powder (m.p. 237°-240° C.) in 25 percent isolated yield (99+ percent by LC). It had the following spectral properties. 1H NMR (250 MHz, DMSO-d6): δ6.7 (d,2H), 6.82 (d,4H), 7.1 (d,4H), 7.75 (d,2H), 7.91 (d, 2H), 8.32 (d,2H), 9.55 (d, 2H, OH). 13C NMR (63 MHz, DMSO-d6): δ115.5, 116.5, 122.6, 124.9, 125.5, 128.4, 136.6, 144.3, 147.4, 153.1, 155.6, 156.9. GCMS (EI) m/z calcd (found) for C24H18N4O4 =426 (426 w/276 at 100 percent).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:21]1[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=3.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.Cl.[F:57][C:58]1([F:63])[CH2:62][CH2:61][NH:60][CH2:59]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:57][C:58]1([F:63])[CH2:62][CH2:61][N:60]([C:2]2[N:7]=[CH:6][C:5]3[O:8][C:9]4[C:14]([C@@:15]5([CH2:19][O:18][C:17]([NH2:20])=[N:16]5)[C:4]=3[CH:3]=2)=[CH:13][C:12]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:11][CH:10]=4)[CH2:59]1
Reactant: FC1(F)CCNC1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCC(F)(F)C3)cc12
Temperature: 90 °C

Procedure:
To a resealable tube charged with a mixture of (S)-3-chloro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.25 g, 0.653 mmol), pd2(dba)3 (0.030 g, 0.033 mmol), 2-(dicyclohexylphosphino)-2′-(n,n-dimethylamino)biphenyl (0.039 g, 0.098 mmol), and 3,3-difluoropyrrolidine hydrochloride (0.281 g, 1.959 mmol) was added 1.0 M lithium bis(trimethylsilyl)amide (3.92 mL, 3.92 mmol) in THF and the resulting mixture was heated at 90° C. for 24 h. The mixture was concentrated and purified by reverse phase HPLC to afford (S)-3-(3,3-difluoropyrrolidin-1-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>ClCCl>[CH:15]1([NH:18][C:12](=[O:13])/[CH:11]=[C:8]2\[CH2:7][CH2:6][C:5]3[C:9]\2=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Solvent: ClCCl
Product: O=C(/C=C1\CCc2ccc(F)cc21)NC1CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
To an ice-cold stirred solution of (E)-2-(6-Fluoro-1-indanylidene)acetyl Chloride in dichloromethane (50 ml) was added cyclopropylamine (1.65 g, 28.86 mmol) and the reaction was warmed to room temperature overnight. The reaction was evaporated in vacuo to a solid residue. This residue was dissolved in ethyl acetate (300 ml), washed with water (75 ml), and the organic layer was concentrated by spin evaporation in vacuo. The residue was chromatographed on silica gel using ethyl acetate-hexanes (0:1 to 1:1 gradient) as eluent. Fractions containing only the product were combined and concentrated by spin evaporation in vacuo. Recrystallization of the residue from dichloromethane-hexanes gave 1.6 g (76%) of (E)-N-cyclopropyl-2-(6-fluoro-1-indanylidene)acetamide as a white powdery solid, m.p. 124°-127° C.; NMR (DMSO-d6): d 8.03 (d, 1H, J=3.9 Hz, NH), 7.45-7.38 (m, 1H, Ar), 7.28-7.14 (m,2H, Ar), 6.30 (s, 1H, =CH, 3.23-3.21 (m, 2H, CH2), 2.99-2.96 (m, 2H, CH2), 2.72 (m, 1H, NCH), 0.71-0.39 (2ms, 4H, CH2 -CH2); steady state nOe: irradiation at d6.30, observed 15% nOe at d 8.03 and 20% nOe at d 7.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][OH:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:23][OH:24])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([F:21])[CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)cc2F)cc1
Yield: 85.6 %

Procedure:
In a manner similar to Example 4, Step (c), 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid (1.100 g, 0.00359 mol) was allowed to react with hydroxylamine hydrochloride (0.300 g, 0.00432 mol) in the presence of sodium carbonate (0.458 g, 0.00432 mol) in absolute ethanol (20 mL) to give 0.989 g of 4-(4′-chloro-2′-fluoro-biphenyl-4-yl)-4-hydroxyimino-butyric acid as an off-white solid; mp 147.5-149.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[O-]CC.[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:7]=1
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-3-buten-2-one (27.1 g) and diethyl oxalate (21.9 g) in dry diethyl ether (200 ml) was added drop-wise over 15 minutes to a stirred suspension of sodium ethoxide (3.45 g of sodium dissolved in absolute ethanol and excess ethanol evaporated off) in dry diethyl ether (400 ml) cooled to 5°-10° C. by an ice bath. A yellow solid began to precipitate after 5 minutes.
Reaction SMILES: COC(=O)COC1C=CC(SC#N)=C(OC)C=1.C[O:19][C:20](=[O:49])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[C:25]([O:47][CH3:48])[CH:24]=1>>[CH3:48][O:47][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=2)=[CH:33][CH:32]=1)[O:22][CH2:21][C:20]([OH:49])=[O:19]
Reactant: COC(=O)COc1ccc(SCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c(OC)c1
Agent: COC(=O)COc1ccc(SC#N)c(OC)c1
Product: COc1cc(OCC(=O)O)ccc1SCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Preparation of 3-Methoxy-4-thiocyanato-phenol (compound 21A) The title compound was prepared in a manner analogous to Example 1B from 3-methoxy-phenol. 400 MHz 1H NMR (DMSO-d6) δ 10.21 (s, 1H), 7.34 (d, 1H, J=8.3 Hz), 6.53 (s, 1H), 6.43 (d, 1H, J=8.3 Hz), 3.81 (s, 3H). Step 2. Preparation of (3-Methoxy-4-thiocyanato-phenoxy)-acetic acid methyl ester (compound 21B) The title compound was prepared from the product of Example 21A in a manner analogous to Example 1C. MS m/z 227 (M-CN). Step 4. Preparation of (4-Mercapto-3-methoxy-phenoxy)-acetic acid methyl ester (compound 21C) The title compound was prepared from (3-Methoxy-4-thiocyanato-phenoxy)-acetic acid methyl ester in a manner analogous to Example 1D. 400 MHz 1H NMR (DMSO-d6) δ 7.13 (d, 1H, J=8.5 Hz), 6.56 (s, 1H), 6.39 (d, 1H, J=8.5 Hz), 4.72 (s, 2H), 4.51 (s, 1H), 3.75 (s, 3H), 3.64 (s, 3H). Step 5. Preparation of [3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid methyl ester (compound 21D) The title compound was prepared in the manner analogous to Example 1F using 3B and 21C. 400 MHz 1H NMR (DMSO-d6) δ 7.81 (d, 2H, J=8.3 Hz), 7.53 (d, 2H, J=8.3 Hz), 7.59 (d, 2H, J=8.3 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.11 (d, 1H, J=8.5 Hz), 6.56 (s, 1H), 6.37 (d, 1H, J=8.5 Hz), 4.73 (s, 2H), 4.04 (s, 2H), 3.76 (s, 3H), 3.63 (s, 3H); MS m/z 463 (M+1). Step 6. Preparation of [3-Methoxy-4-(4′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-phenoxy]-acetic acid (compound 21) The title compound was prepared in the manner analogous to Example 1 using 21D. 400 MHz 1H NMR (DMSO-d6) δ 7.83 (d, 2H, J=8.3 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.61 (d, 2H, J=8.3 Hz), 7.34 (d, 2H, J=8.3 Hz), 7.13 (d, 1H, J=8.5 Hz), 6.56 (s, 1H), 6.39 (d, 1H, J=8.5 Hz), 4.63 (s, 2H), 4.06 (s, 2H), 3.77 (s, 3H); MS m/z 449 (M+1). Anal. Calc'd for C23H19F3O4S, C, 61.60; H, 4.27; found: C, 61.35; H, 4.25.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C1CCC(CO)CC1
Product: CC(=O)OCC1CCC(C(C)(C)O)CC1

Procedure:
treating 7,8-dihydroxy-p-menthane with acetic anhydride to give 7-acetoxy-8-hydroxy-p-menthane;
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH2:15]([NH:17][CH2:18][C:19]12[CH2:26][CH2:25][CH2:24][N:23]1[CH2:22][CH2:21][CH2:20]2)[CH3:16].[I-].[Na+].[OH-].[Na+]>N1C=CC=CC=1>[N:23]12[CH2:24][CH2:25][CH2:26][C:19]1([CH2:18][N:17]([C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1)[CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22]2
Reactant: O=[N+]([O-])c1ccc(Cl)c2ccccc12
Reactant: CCNCC12CCCN1CCC2
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCN(CC12CCCN1CCC2)c1ccc([N+](=O)[O-])c2ccccc12
Yield: 30.6 %

Procedure:
1-Chloro-4-nitronaphthalene (2.00 g, 9.63 mmol), 5-ethylaminomethyl-1-azabicyclo[3.3.0]octane (3.24 g, 19.3 mmol) and sodium iodide (580 mg) were added into anhydrous pyridine (20.0 ml) to react the mixture in a sealed tube for 20 hours at 190° C. After addition of aqueous sodium hydroxide solution subsequent to concentration in vacuo, the reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatography to afford the desired compound (1.00 g, 30.6%), as a yellow liquid.