Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[NH2:2].[C:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].N1CCOCC1.C(O)(C(F)(F)F)=O>CO.ClCCl>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][C:25]2([NH:2][C:1](=[O:3])[C:4]3[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:13]=3[O:14]2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1ccc(O)c(C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Yield: 39.1 %

Procedure:
A mixture of 125 mg (0.64 mmol) of methyl 3-carbamoyl-4-hydroxybenzoate, 192 mg (0.96 mmol) of 1-Boc-4-piperidone, and 120 μL of morpholine in 10 mL of MeOH is refluxed for 72 hr. The MeOH is removed by rotoevapoation, and DCM is added to the residue. Insoluble material is filtered off, and the filtrate is concentrated by rotoevaporation. The residue is purified by preparative TLC to give 93 mg (0.25 mmol, 39% yield) of 1′-(tert-butyloxycarbonyl)-6-methoxycarbonylspiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one which on treatment with 40% TFA in dichloromethane gives the TFA salt of 6-methoxycarbonylspiro[1,3-benzoxazine-2,4′-piperidine]-4(3H)-one in quantitative yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: COc1ccc2c(O)ccnc2c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(O)c(CO)cnc2c1
Reaction time: 18 h

Procedure:
4-Hydroxy-7-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide (initially at 40°-50°, then kept at 60° for 18 hours) to give the novel compound 4-hydroxy-3-hydroxymethyl-7-methoxyquinoline, m.p. 291°-297°.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:18]=[N:19][C:20]([CH:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([O:33]CC)=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)[CH3:24])=[N:21][CH:22]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O.[Cl-].[Na+].O>[F:37][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:11]=[C:12]([C:17]3[CH:22]=[N:21][C:20]([CH:23]([CH:25]4[CH2:30][CH2:29][C@@H:28]([C:31]([OH:33])=[O:32])[C@@H:27]([CH3:36])[CH2:26]4)[CH3:24])=[N:19][CH:18]=3)[CH:13]=[C:14]([CH3:16])[CH:15]=2)[N:4]=1
Reactant: CCOC(=O)[C@@H]1CCC(C(C)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)F)n4)c3)cn2)C[C@@H]1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnc(C(C)C3CC[C@@H](C(=O)O)[C@@H](C)C3)nc2)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylate, isomer 1 (22 mg, 0.044 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (5.0 mg, 0.13 mmol). The reaction mixture was stirred for 8 hours at 60° C. and then cooled to room temperature. The pH of the mixture was adjusted to pH 2 by adding aqueous hydrochloric acid, and then the mixture was diluted with brine and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give rel-(1R,2S)-4-{1-[5-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)pyrimidin-2-yl]ethyl}-2-methylcyclohexanecarboxylic acid. MS ESI calc'd. for C26H30F2N5O2 [M+H]+ 482. found 482. 1H NMR: (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.97 (s, 2H), 8.72 (s, 1H), 8.00 (s, 1H), 7.59 (s, 1H), 7.22 (s, 1H), 7.08-7.07 (m, 1H), 6.88 (t, J=54.4 Hz, 1H), 2.79-2.76 (m, 1H), 2.36 (s, 3H), 2.07-1.43 (m, 8H), 1.24-1.23 (m, 3H), 0.92-0.91 (m, 1H), 0.85-0.83 (m, 3H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][NH:15]4)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:13][N:14]4[C:19]=3[CH2:18][CH2:17][CH2:16][N:15]4[C:27](=[O:29])[CH3:28])[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(NC4CC4)n2)CCCN3)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21

Procedure:
A catalytic amount of 4-dimethylaminopyridine (ca. 5 mg) was added to a solution of N-cyclopropyl-4-[2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine (i.e. the product of Step E) (42.1 mg, 0.12 mmol) and acetic anhydride (0.023 mL, 0.24 mmol) in 2 mL of pyridine at room temperature. After 3 h the reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluent to give 25 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[C:7]([CH3:10])[C:6]([OH:11])=[C:5]([CH3:12])[C:4]=1[Br:13].CC1C=C(C)C=C(C)C=1O.BrBr.[Br:26]C1C(C)=C(O)C(C)=C(Br)C=1C>C(O)(=O)C.C([O-])(=O)C.[Na+].C(O)(=O)C.O>[Br:13][C:4]1[C:3]([Br:26])([CH3:2])[C:8]([Br:9])=[C:7]([CH3:10])[C:6](=[O:11])[C:5]=1[CH3:12]
Reactant: Cc1c(O)c(C)c(Br)c(C)c1Br
Reactant: Cc1c(O)c(C)c(Br)c(CBr)c1Br
Agent: BrBr
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(O)c(C)c1
Solvent: O
Solvent: CC(=O)O
Product: CC1=C(Br)C(C)(Br)C(Br)=C(C)C1=O

Procedure:
The preparation of a halogenated phenol such as 4-bromomethyl-3,5-dibromo-2,6-dimethylphenol (tribromomesitol) can involve the following sequence: bromination of 2,4,6-trimethylphenol (mesitol) with 2 moles of bromine in acetic acid to prepare 3,5-dibromo-2,4,6-trimethylphenol (dibromometisol) which is isolated by precipitation with water. K. Auwers & F. Rapp, Ann., 302, 153-71 (1898) and O. Jacobsen, Ann., 195, 265-92 (1879); the dibromomesitol is brominated in acetic acid sodium acetate buffer at low temperatures to afford an intermediate, 3,4,5-tribromo-2,4,6-trimethyl-2,5-cyclohexadienone, which is isolated by fast precipitation with water and filtration; this solid slowly rearranges to tribromomesitol at room temperature, more quickly at higher temperatures. K. Fries & E. Brandes, Ann., 542, 48-77 (1939). This procedure to prepare tribromomesitol is complex and not industrially viable.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl.C(O)(=O)C>[CH:1]1([NH:4][CH:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.5 %

Procedure:
To a mixture of 3.35 g of cyclopropylamine, 1.0 mL of acetic acid, 9.34 g of sodium triacetoxyborohydride, and 30 mL of 1,2-dichloroethane was added dropwise 5.00 g of ethyl 4-oxocyclohexane carboxylate at room temperature. After stirring at room temperature for 14 hours, to the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution to quench the reaction. To the reaction mixture was added chloroform, followed by extraction and then the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (aqueous ammonia-methanol-chloroform) to obtain 5.62 g of ethyl 4-(cyclopropylamino)cyclohexane carboxylate as a colorless oily substance.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1(O)C=CC=CC=1.C1(C(C2C=CC=C(C)C=2C)C)C=CC=CC=1.[C:32](=[O:34])=[O:33]>O>[C:32]([OH:34])(=[O:33])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: O=C=O
Reactant: [O-]c1ccccc1
Agent: Cc1cccc(C(C)c2ccccc2)c1C
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: O=C(O)c1ccccc1O

Procedure:
In a pressure reaction vessel were charged 100 g of sodium phenolate, 40 g of phenol and 400 g of 1-phenyl-1-(2,3-dimethylphenyl)-ethane, and a reaction was allowed to proceed at 170° C. and at a carbon dioxide pressure of 10 kg/cm2 (G) for 2 hours, with stirring. The reaction mixture was cooled and charged into 500 ml of water, followed by separation into the reaction medium layer and the water layer at 90° C. The water layer was extracted with 50 g of xylene, and the phenol was recovered with an aqueous sodium hydroxide solution from the reaction medium and extraction medium layers. After recovery of phenol, the water layer was made acid with dilute sulfuric acid to give 94.3 g of salicylic acid, with neither p-hydroxybenzoic acid nor isophthalic acid being detected as an isomer. The yield based on sodium phenolate was 90.2%, and the recovered phenol was 57 g, with the selectivity being 98.5%.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[I-].[NH2:8][N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#[CH:20].C(Cl)Cl>CN(C=O)C>[CH2:15]([C:10]1[N:9]2[N:8]=[CH:20][C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])=[C:14]2[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH3:17]
Reactant: C#CC(=O)OCC
Reactant: CCCc1cccc[n+]1N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1cccc2c(C(=O)OCC)cnn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
Next, 2.41 g (22.7 mmol) of Na2CO3 were added to a solution of 5.0 g (18.9 mmol) of 1-amino-2-propylpyridinium iodide in 20 ml of DMF, followed by stirring at room temperature for 1 hour. Ethyl propiolate (3.71 g; 37.9 mmol) was added further, followed by stirring at room temperature for 20 hours. After the reaction, the reaction mixture was treated in a similar manner to the preparation of the 7-ethyl derivative, whereby 1.45 g (6.25 mmol) of the title compound were obtained as crystals from CH2Cl2 :hexane=1:1 eluate fractions (yield: 33% - 9% in two steps).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C.C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.Cl[Rh+]C1(C)C(C)=C(C)C(C)=C1C>[Cl:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: CC1=C(C)C(C)([Rh+]Cl)C(C)=C1C
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=CO
Product: O[C@H](CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
2-Chloroacetophenone (154.0 mg, 1.0 mmol) and a formic acid/triethylamine azeotropic mixture (0.2 ml) were added to a solution of chloro(pentamethylcyclopentadienyl)rhodium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (0.67 mg, 0.001 mmol, s/c=1000) in ethyl acetate (1.0 ml), followed by stirring at room temperature for 2 hours. After completion of the reaction, purification by silica gel column chromatography furnished a desired compound, (S)-(+)-2-chloro-1-phenylethanol (145.1 mg; yield: 93.0%; optical purity: 96.6% ee).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.S(=O)(=O)(O)O>ClCCl>[O:14]=[C:3]1[C:2]2[N:1]=[C:21]([C:20]3[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[O:22][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(o2)C(=O)c2ccccc2C3=O)cc1
Yield: 56 %

Procedure:
To a solution of 5.0 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 80 mL of dichloromethane, one adds, with protection from light and at ambient temperature, 16 mL (120 mmol) of 4-methoxybenzoic acid chloride, then 0.003 mL of concentrated sulfuric acid. After 3 h of reflux, the reaction mixture is evaporated to dryness; the black oily residue obtained is redissolved in 300 mL of dichloromethane, washed with a solution of 10N sodium hydroxide, then with water, and finally dried over calcium chloride. The product is then purified on a flash column (support: silica 6-35 mm; conditioning: heptane; eluant: dichloromethane/heptane, 60/40), to produce 4.1 g of 4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphtho[2,3-d]oxazole in the form of yellow-orangish crystals after recrystallization and color removal with animal charcoal.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[O:2]2.C(O)(=O)C>N1C=CC=CC=1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[O:2]2
Reactant: O=C(OCc1ccccc1)N1OC2C=CC1C2
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1OC2CCC1C2
Temperature: 25 °C
Yield: 83.4 %

Procedure:
Azodicarbonamide (5.0 g) was stirred with a solution of potassium hydroxide (7.0 g) in water (12 ml) at 4°. After stirring in the ice bath for 1 h the mixture was diluted with ice/water (30 ml) and the solution was filtered. The filtrate was diluted with cool (2°) ethanol (100 ml) and the resultant solid was filtered off, washed with ethanol, methanol and ether to give potassium azodicarboxylate (6.9 g). This was then mixed with 3-aza-2-oxabicyclo[2.2.1]hept-5-ene-3-carboxylic acid, (phenylmethyl) ester (0.82 g) in dry pyridine (60 ml), and acetic acid (2.02 g) was added with stirring at room temperature. After one hour a further portion of glacial acetic acid (2.02 g) was added and the reaction mixture was stirred for 15.5 h. The mixture was evaporated to dryness under reduced pressure. Further acetic acid was then added to quench the remaining yellow colour of the diimide precursor. The residue was partitioned between 0.5M citric acid (75 ml) and ethyl acetate (75 ml) and the organic phase was separated, dried, and concentrated in vacuo. The residue was purified by FCC eluting with ethyl acetate:cyclohexane (1:2) to give the title compound (0.69 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[CH3:21])[N:7]=[C:6]([NH:15][C@H:16]([CH2:18][CH3:19])[CH3:17])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(NS(C)(=O)=O)n1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)Nc1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
Treat a mixture of (s)-(+)-2-sec-butylamino-6-methanesulfonylamino-isonicotinic acid methyl ester (13.63 g, 0.04523 mol) and potassium carbonate (12.50 g, 0.09046 mol) in DMF (42 mL) with iodomethane (7.90 g, 0.05563 mol). Stir at room temperature for 18 h, and add water (200 mL). The aqueous layer was extracted with methyl tert-butyl ether (5×150 mL). Wash the combined organic layers with 1 N lithium chloride (5×100 mL), dry (magnesium sulfate) and concentrate to give the title compound as a solid (13.19 g, 92%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[S:8][CH:9]=[C:10]([Br:12])[N:11]=1>>[Br:6][C:7]1[S:8][C:9]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:10]([Br:12])[N:11]=1
Reactant: O=S(=O)(O)Cl
Reactant: Brc1csc(Br)n1
Product: O=S(=O)(Cl)c1sc(Br)nc1Br
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
To a flask containing chlorosulfonic acid (51.0 mL, 767 mmol) was added 2,4-dibromothiazole (10.2 g, 42.0 mmol) with stirring over 15 minutes. The resulting solution was heated to 150 degrees overnight. The reaction was quenched by carefully and slowly pouring onto ice (500 mL). The resulting precipitate was extracted with ethyl acetate (2×200 mL) and the combined organic layers were washed with water, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexane=0/100→15/85) to give 8.1 g (56% yield) of the title compound as a yellow oil which partially solidified. 13C NMR (400 MHz, CDCl3) δ: 145.04, 138.78, 131.81.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[OH:15][C:16]1[CH:17]=[C:18]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][O:15][C:16]3[CH:17]=[C:18]([C@@:22]4([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]4)[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][C:8]1=[O:14]
Reactant: CO[C@]1(c2cccc(O)c2)CCO[C@@H](C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CO[C@]1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCO[C@@H](C)C1
Yield: 69 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2S,4R)-4-(3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-[3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran in 69% yield, m.p. 88°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4].[C:24](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([CH3:24])[C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][N:6]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1CC(NC(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CC(N(C)C(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(2,2,2-Trifluoro-acetylamino)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.26 g, 0.76 mmol) in DMF (2 mL) was added potassium carbonate (0.139 g, 1 mmol) followed by methyl iodide (0.14 g, 1 mmol). The reaction mixture was stirred at 80° C. for 16 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (50% ethyl acetate in Hexanes) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[Cl:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:6](=[O:15])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:13]=1[CH:24]=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)ccn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nccc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
To (4-chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (CB Research and Development Inc., 2.0 g, 8.75 mmol) in THF (18 mL) under nitrogen at −78° C., was added n-BuLi (13.7 mL, 21.9 mmol, 1.6 M in hexanes) dropwise. After stirring at −78° C. for 45 min, a solution of DMF (1.93 mL) in THF (2 mL) was added dropwise. The reaction was stirred at −78° C. for 30 min and was then allowed to warm slowly to room temperature. The reaction was quenched with 1N aq HCl solution and then basified with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtOAc) to afford the title compound (0.95 g, 42%) as a white solid. 1H NMR (DMSO-d6) δ 10.44 (s, 1H), 10.13 (s, 1H), 8.47 (d, 1H, J=5.2 Hz), 7.40 (d, 1H, J=5.6 Hz), 1.48 (s, 9H).
Reaction SMILES: [N:1]([CH:4]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>C(O)C.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][CH:4]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[NH2:1])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(F)cc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(N)c2ccc(F)cc2)CCN(C)C1
Temperature: 100 °C
Yield: 78.7 %

Procedure:
To a solution of 5-(2-azido-2-(4-fluorophenyl)ethyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 2.75 mmol) in ethanol-water (40-5 mL) was added ammonium chloride (590 mg, 11.02 mmol) and zinc dust (716 mg, 11.02 mmol) and heated at 100° C. for 1 h. After complete conversion of starting material (TLC), ethanol was removed under reduced pressure and 50 mL additional water was added and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase HPLC to obtain 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(4-fluorophenyl)ethanamine (730 mg) as the TFA salt. 1H NMR (CD3OD, TFA salt): δ (ppm): 7.27 (m, 1H), 7.21 (m, 3H), 7.10 (m, 3H), 4.60 (m, 3H), 4.50 (m, 1H), 4.24 (m, 1H), 3.69 (m, 1H), 3.44 (m, 1H), 3.04 (m, 1H), 2.96 (s, 3H), 2.56 (m, 1H), 2.41 (s, 3H). Chiral HPLC separated the racemate into enantiomers II-11a-b.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([CH3:13])=[CH2:12])[C:5](I)=[N:6][CH:7]=1.C([O-])=O.[Na+].C(N(CC)CC)C.CS(C)=O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: C=C(C)CNc1cc(Br)cnc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)CNc2cc(Br)cnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
A mixture of (5-bromo-2-iodo-pyridin-3-yl)-(2-methyl-allyl)-amine (10.2 g, 28.9 mmol), tetrabutylammonium chloride (9.64 g, 34.7 mmol), sodium formate (2.36 g, 34.7 mmol), palladium acetate (0.97 g, 4.3 mmol), triethylamine (8.76 g, 86.7 mmol), water (12.1 mL) and dimethyl sulfoxide (255 mL) was stirred at 100° C. under nitrogen for 1 h. The mixture was cooled by the addition of ice (100 g) then was diluted with water (200 mL) with stirring. The mixture was partitioned between water (1 L) and a mixture of toluene (600 mL) and EtOAc (50 mL). The organic phase was washed with water (4×250 mL), dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography (SiO2, gradient elution with 0-100% diethyl ether in 40-60 petroleum ether) gave the title compound (2.84 g) as a yellow solid. MS: [M+H]+=227, 229.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][CH2:9][C@H:10]1[N:15]([CH3:16])[C:14](=[O:17])[CH2:13][O:12][CH2:11]1
Reactant: [H][H]
Reactant: CN1C(=O)COC[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)COC[C@H]1CO
Yield: 96.1 %

Procedure:
Prepare a slurry containing 10% Pd/C (137 mg) in MeOH (50 mL). Add a solution of (R)-5-benzyloxymethyl-4-methyl-morpholin-3-one (1.3 g, 5.5 mmol) in MeOH (100 mL). Pressurize with hydrogen gas (50 psi) and stir for 2 h. Filter the reaction through Celite® and elute with MeOH. Concentrate the filtrate to give 767 mg (96%) of the title compound. MS/ES m/z 146.1 [M+H]+.