Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[BH4-].[Na+]>C(#N)C.C(O)(C)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH2:3][C@@H:2]([NH2:1])[CH3:14])=[CH:6]1
Reactant: C[C@H](N)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)O
Product: C[C@H](N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of (S)-2-amino-1-(1H-indol-3-yl)-propan-1-one (0.47 g, 2.5 mmol, 1.0 eq.) in acetonitrile and isopropanol is treated portionwise with NaBH4 (285 mg, 7.49 mmol, 3.0 equiv.), heated at reflux temperature for 24 h, stirred at room temperature under N2 for 36 h, quenched with methanol, concentrated and partitioned between water and EtOAc. The EtOAc phase is dried over MgSO4 and concentrated in vacuo to afford the title product as a brown oil, identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([O:15][CH2:16][CH2:17][CH2:18]O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH2:8]([O:15][CH2:16][CH2:17][CH2:18][N:3]1[C:4](=[O:6])[CH2:5][NH:1][C:2]1=[O:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCCOCc1ccccc1
Reactant: O=C1CNC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CNC(=O)N1CCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
Imidazolidine-2,4-dione (1.0 g, 9.99 mmol), 3-benzyloxypropan-1-ol (1.91 ml, 12.0 mmol) and triphenylphosphine (3.1 g, 12.0 mmol) were stirred in methylene chloride (20 ml) and cooled to 0° C. Diisopropyl azodicarboxylate (2.36 μl, 12.0 mmol) in dichloromethane (5 ml) was slowly added and the mixture stirred at ambient temperature overnight. The mixture was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2) to give 3-(3-benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 53%, containing 7% w/w triphenylphosphine oxide) as a pale yellow solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24](O)=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34]1>>[CH:1]([N:14]1[CH2:15][CH:16]([CH2:18][O:19][C:20]2[C:28]([CH:29]3[CH2:31][CH2:30]3)=[CH:27][C:23]([C:24]([NH:39][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])=[O:25])=[C:22]([F:32])[CH:21]=2)[CH2:17]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F

Procedure:
The compound was prepared in a similar manner to Example 408 from 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid and cyclopropanesulfonamide. LCMS (Method D): RT=4.69 min, m/z: 535.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.48-7.36 (m, 4H), 7.28 (t, J=7.4 Hz, 4H), 7.23-7.09 (m, 3H), 6.96 (d, J=12.8 Hz, 1H), 4.50 (s, 1H), 4.22 (d, J=6.1 Hz, 2H), 3.12-2.96 (m, 3H), 2.94-2.80 (m, 1H), 2.12-1.99 (m, 1H), 1.18-0.97 (m, 4H), 0.95-0.82 (m, 2H), 0.73-0.60 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([NH2:11])=[CH:9][CH:10]=1)=[O:4].N1C=CC=CC=1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C(#N)C>[C:19]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:12][C:7]2[C:8]([NH2:11])=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Reaction time: 3 h

Procedure:
To a stirring solution of 4-methoxycarbonyl-1,2-benzenediamine (8.5 g, 51 mmol) and pyridine (4.1 mL, 51 mmol) in acetonitrile (225 mL) at 0° C. was added via an addition funnel a solution of 4-t-butylbenzoyl chloride (10 g, 51 mmol) in acetonitrile (25 mL). After 3 h, the mixture was concentrated to a volume of about 20 mL in vacuo and then diluted with ethyl acetate (300 mL) and water (100 mL). The phases were separated and the organic phase was washed twice with 1 M citric acid, once with brine, twice with satd aq NaHCO3 and once again with brine. The organic phase was then dried with MgSO4, filtered and partially concentrated in vacuo. After standing for 48 h, the resulting precipitate was filtered, washed with ethyl acetate and dried in vacuo to give 8.2 g (48%) of off white solid. By a similar procedure, a second crop of 2.6 g (16%) was isolated from the mother liquor.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:17]O)[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[Br:19]P(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[N:6][CH:5]=[C:4]([CH2:17][Br:19])[CH:3]=1
Reactant: OCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(Oc2ncc(CBr)cc2Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A solution of the product from Example 60B (0.73 g, 2.309 mmol) in dichloromethane (11.55 mL) under nitrogen was treated dropwise with tribromophosphine (0.218 mL, 2.309 mmol), stirred for one hour and poured into ice water and the pH was adjusted to pH 9 by addition of solid sodium bicarbonate added portionwise. An emulsion formed that was partially removed by filtration. The aqueous layer was extracted with dichloromethane and the organics were combined, washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4) filtered, and concentrated to afford the title compound (0.75 g, 86%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[O:3]1.[NH4+:15].[OH-]>S(Cl)(Cl)=O.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([CH2:11][C:12]([NH2:15])=[O:14])[O:3]1
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)CC1OC(=O)c2ccccc21

Procedure:
A solution of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetic acid (5.0 g, 26 mmol) in thionyl chloride (10 ml) was heated at 75° C. for 15 minutes. The excess thionyl chloride was removed under vacuum to give a red oil. The red oil was dissolved in CH2Cl2 (10 ml) and then the solution was slowly added to concentrated NH4OH (40 ml) at 0° C. The resultant solid was filtered and washed with water and hexane, followed by addition of toluene. Removal of the solvent led to 2-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetamide as a cream solid (4.2 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH3:13][C:14](=[CH2:27])[CH2:15][S:16][C:17]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([S:16][CH2:15][C:14]([CH3:27])=[CH2:13])[CH:22]=1
Reactant: C=C(C)CSc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
A mixture of 1.85 g (0.00939 mole) of 2-chloro-4-trifluoromethylphenol (Example 1, Part A), 2.1 g (0.0093 mole) of 2-(2-methyl-2-propenylthio)-4-fluoronitrobenzene (Part A), and 1.3 g (0.0094 mole) of potassium carbonate in 25 ml of dimethyl formamide was stirred at 60° C. for three hours. The mixture was poured into water and extracted with chloroform. The chloroform extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the chloroform was evaporated under reduced pressure. The residue was subjected to a hagh vacuum, leaving 2.5 g of 3-(2-methyl-2-propenylthio)-4-nitrophenyl 2-chloro-4-trifluoromethylphenyl ether as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][NH:11][C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: NCCC#Cc1ccccn1
Reactant: Clc1nc2ccccc2s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C(#Cc1ccccn1)CCNc1nc2ccccc2s1
Temperature: 120 °C
Yield: 94.7 %

Procedure:
4-(pyridin-2-yl)but-3-yn-1-amine (640 mg, 4.40 mmol), 2-chlorobenzo[d]thiazole (373 mg, 2.2 mmol) and DIEA (452 μL, 2.64 mmol) were poured into DMF (2.2 mL) and the resulting solution was heated two days at 120° C. The solvent was removed under reduce pressure and the crude product was purified over silicagel chromatography (prepacked 25 g silicagel column, Cyclohexane/AcOEt: 70/30 as eluent) to afford 582 mg of N-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazol-2-amine (Yield: 95%) as a brownish oil.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][O:18][C:19](=[O:45])[C:20]([CH3:44])([CH3:43])[CH2:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](O)=[O:41])=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>CN(C)C=O>[CH3:44][C:20]([CH3:43])([CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:38]=[C:37]3[C:32]([C:33]([C:40](=[O:41])[NH:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:34][C:35]([CH3:39])=[N:36]3)=[CH:31][CH:30]=2)=[CH:27][N:28]=1)[C:19]([O:18][CH3:17])=[O:45]
Reactant: Nc1ccccc1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)O)cc(C)nc3c2)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc3c(C(=O)Nc4ccccc4)cc(C)nc3c2)cn1
Reaction time: 8 h
Yield: 88 %

Procedure:
N-Ethyl-N,N-diisopropylamine (64.5 mg, 0.50 mmol) was added at room temperature to a solution of aniline (465.0 mg, 0.50 mmol), 7-(6-(3-methoxy-2,2-dimethyl-3-oxopropoxy)pyridin-3-yl)-2-methylquinoline-4-carboxylic acid B-15 (98.8 mg, 0.25 mmol) and N,N,N′N-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (190.0 mg, 0.50 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, then partitioned between methylene chloride (30 mL) and an aqueous solution of pH 7 phosphate buffer (30 mL). The aqueous layer was extracted with methylene chloride (3×30 mL); the combined extracts were successively washed with water (30 mL), brine (30 mL), then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give methyl 2,2-dimethyl-3-(5-(2-methyl-4-(phenylcarbamoyl)quinolin-7-yl)pyridin-2-yloxy)propanoate B-16 (103.4 mg, Yield=88%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 6H), 2.83 (s, 3H), 3.73 (s, 3H), 4.42 (s, 2H), 6.90 (d, J=8.5 Hz, 1H), 7.26-7.29 (m, 1H), 7.45-7.48 (m, 3H), 7.73-7.77 (m, 2H), 7.88 (s, 1H), 7.95 (q, J=6.0 Hz, 1H), 8.23 (s, 1H), 8.32 (d, J=8.5 Hz, 1H), 8.54 (s, 1H); MS (ESI) [M+1]+ 470.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=[CH:4][N:3]=1.[NH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][NH2:17])[CH:7]=1
Reactant: NN
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(NN)ncn1

Procedure:
[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-hydrazine was prepared from 4-Chloro-6-(2-methoxy-phenyl)pyrimidine (2.4 g, 11 mmol), hydrazine (1.3 mL, 43 mmol) and potassium carbonate (2.2 g, 16 mmol) in 25 mL of dioxane by a procedure similar to example 3, step 1 yielding 2.0 g (86%) of a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(NC(C)C)(C)C>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.[Cu]I.C1COCC1>[N:10]1([C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccc(I)cc1)N1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 57 °C
Yield: 99.8 %

Procedure:
To a mixture under Ar of (4-iodo-phenyl)-morpholin-4-yl-methanone (273 mg), trimethylsilylacetylene (169 mg), [PdCl2(PPh3)2] (30 mg) and copper(i) iodide (15 mg) is added a degassed mixture of THF (4.5 ml) and diisopropylamine (4.5 ml). After stirring over night at 57° C. and aqueous work up, the organic layer is dried over Na2SO4 and the solvent is evaporated. Flash chromatography (silica gel, CH2Cl2/MeOH/25% NH4OH 97:3:0.3) yields 247 mg of morpholin-4-yl-(4-trimethylsilanylethynyl-phenyl)-methanone as a light brown solid, 1H-NMR (300 MHz): 0.26 (s, 3H); 3.32-3.91 (br, 8H); 7.34 (d, J=6.5, 2H); 7.51 (d, J=6.5, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])=O)(C)(C)C.[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[C:20]1=[O:37]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14].[OH:16][CH2:17][CH2:18][N:19]1[C:24](=[O:25])[CH2:23][CH2:22][CH:21]([N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:20]1=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound obtained in example 16 (658 mg) was dissolved in 25% TFA/DCM solution (10 mL). The mixture was stirred on a magnetic stirrer for 4 hrs at room temperature. DCM and most of TFA were removed by rotary evaporation in vacuo. The foam obtained was dissolved in DCM (50 mL). The resultant mixture was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and filtered. The solid obtained (380 mg) was dried in vacuo. 1H NMR (CDCl3, ppm) δ 8.0-8.1 (m, 2H), 7.90-8.00 (m, 2H), 5.20-5.28 (m, 1H), 4.59-4.62 (m, 1H), 4.30-4.55 (m, 2H), 4.00-4.30 (m, 2H), 3.70-3.85 (m,1H), 3.40-3.65 (m, 2H), 2.90-3.12 (m, 2H), 2.70-2.90 (m, 1H), 2.30-2.50 (m, 1H), 2.00-2.20 (m, 4H)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18]Br)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[Br:1][C:2]1[C:3](=[O:25])[NH:4][C:5]([C:11]2[CH:16]=[C:15]([C:17](=[O:20])[CH2:18][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[CH:14]=[CH:13][C:12]=2[O:21][CH2:22][CH2:23][CH3:24])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CN1CCNCC1
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Product: CCCOc1ccc(C(=O)CN2CCN(C)CC2)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 71 with N-methyl piperazine, in the same manner as that of example 72. 1H NMR (CDCl3) δ: 9.23 (1H, d), 8.19 (1H, dd), 7.10 (1H, d), 4.28 (2H, t), 3.77 (2H, s), 3.53 (1H, m), 2.66 (4H, t), 2.52 (4H, t), 2.31 (3H, s), 2.02 (2H, m), 1.29 (6H, d), 1.15 (3H, t).
Reaction SMILES: [O:1]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4](O)[CH2:3][CH2:2]1.C1C=CC(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:26]([CH:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:1][CH2:2][CH2:3]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OC1CCOc2ncccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC1CCOc2ncccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ol (3.31 mmol) in 16.5 mL toluene were added DPPA (4.96 mmol) followed by DBU (4.96 mmol) at 0° C. The cooling bath was removed after 2 h and the mixture was stirred at RT overnight. The reaction was quenched by adding sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired product as colorless oil;
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].FC1C=CC(C2(O)ONC(CN3CCC(N4C5C=CC(Cl)=CC=5NC4=O)CC3)=C2O)=CC=1>C(O)C.O>[OH2:3].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2=C(O)C(O)(c3ccc(F)cc3)ON2)CC1
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
A 46.5 g-quantity of the above compound (free base) is dissolved in 200 ml of ethanol, and a solution of 15 g of L-tartaric acid in 200 ml of water is added to the ethanol solution. The resulting mixture is allowed to stand at room temperature. The crystals thus precipitated are recrystallized three times from ethanol-water (6:4) to give tartrate monohydrate as colorless prisms. The tartrate monohydrate is treated with an aqueous solution of sodium bicarbonate to give (-)-1-[5-(4-fluorophenyl)-4,5-dihydroisoxazol-3-ylmethyl]-4-(5-chloro-2-oxo-1-benzimidazolinyl)piperidine. Melting point: 143°-145° C. [α]D25 : -108.8 (chloroform).
Reaction SMILES: O[CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21].[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32]>C(OCC)(=O)C.CCCCCC>[F:23][C:24]([F:33])([F:34])[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH:2]1[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:21])[CH3:22]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2O
Reactant: Nc1ccccc1OC(F)(F)F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Nc1ccccc1OC(F)(F)F
Yield: 73 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 235 and (2-(trifluoromethoxy)phenyl)amine, the title compound was synthesized in the same manner as in Example 297. Yield: 73%. Melting point: 196-197° C. (ethyl acetate-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A suspension of Example A8 (0.300 g, 0.754 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), K2CO3 (0.200 g, 1.447 mmol) in a mixture of dioxane/water (10:1) (11 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with Pd(PPh3)4 (0.020 g, 0.017 mmol) and heated at 100° C. under argon over night. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer separated and the aqueous layer extracted with dichloromethane (2×15 mL). The combined organics were dried and concentrated to a small volume and purified by silica gel chromatography (0-100% THF/DCM) to provide 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.152 g, 45%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98-7.94 (m, 4H), 7.74 (d, J=8.8 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.23 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.37 (s, 3H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:15]([O-])=O.[Na+].Cl[Sn]Cl.O>Cl.O>[NH:1]([C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH2:15]
Reactant: O=N[O-]
Reactant: Nc1cc2ccccc2cc1C(=O)O
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cc2ccccc2cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-amino-2-naphthoic acid (15 g, 66.8 mmol) in conc. HCl (100 ml) and water (100 ml) at 0° C. was added NaNO2 (9.22 g, 69 mmol) in 1 g portions while maintaing the reaction temperature below 0° C. After 30 min below 0° C., SnCl2·H2O (75 g) was added in portions over 20 min. The ice bath was removed and stirred at ambient temperature for 1 h. Reaction was filtered and the filter cake washed with water and air dried. The crude material containing tin (II) salts was used as is and gave a mp>300° C.
Reaction SMILES: [Mg].C(Br)Br.Cl[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]([CH:6]3[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)([OH:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=C1c2ccccc2COc2cc(Br)ccc21
Agent: [Mg]
Solvent: BrCBr
Solvent: C1CCOC1
Product: CN1CCC(C2(O)c3ccccc3COc3cc(Br)ccc32)CC1

Procedure:
Magnesium turnings (3.42 g, 143 mmol) were suspended in 15 mL of dry THF under nitrogen. To this was added CH2Br2 (1.25 mL, 14.5 mmol) and a vigorous reaction was observed. The reaction was heated to reflux, and 4-chloro-1-methyl-piperidine (21 mL, 128 mmol) was added. The reaction was refluxed for 1 h. The reaction was allowed to cool, and the supernatant was transferred via cannula to a stirring solution of compound 2c (8 g, 128 mmol) in THF at room temperature. The slurry was rinsed with 2×20 mL THF and the supernatant was transferred. At that time, all of the starting ketone had been consumed. To the reaction was added saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude product Compound 1d was used without further purification. MS m/z (MH+) 388.14.