Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[S:12])=[C:30]([CH3:35])[C:29]=1[CH3:36]
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[N:14]([C:15](=O)[C:6]=2[CH:5]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3)([O-:3])=[O:2].B.[ClH:20]>C1COCC1.C(O)C>[ClH:20].[N+:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH2:8][CH:9]3[N:14]([CH2:15][C:6]=2[CH:5]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3)([O-:3])=[O:2]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2CC2CCCCN12
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)CN1CCCCC1C2
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of 8-nitro-1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizin-6-one (4.18 g, 17.0 mmol) in anhydrous THF (50 ml) was added 1.0M borane i THF (50 ml). The reaction mixture was heated at reflux for 18 h. After cooling to room temperature, the excess borane was quenched by the addition of methanol and 6M hydrochloric acid (6 ml) and the solution was heated for 2 h. The solvent was removed in vacuo and the residue was taken up in water. The resulting solution was basified with sodium hydroxide and extracted twice with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give an oil which was immediately taken up in ethanol (60 ml). Hydrochloric acid in ethanol was added until the solution was distinctly acidic and the solution was stirred for several hours at ambient temperature. The precipitate was collected, washed with ethanol, and air-dried to give the title compound as a white solid (3.03 g, 70%), m.p. 245-7° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:4][C:3]([N:2]([CH3:1])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:5][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CN(C(N)=S)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(N(C)c2ccccc2)nc1C
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 1-methyl-1-phenyl-thiourea (5.03 g, 30.3 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.4 mL, 31.8 mmol) in ethanol (18 mL) was refluxed for 20 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a brown solid (7.39 g): MS: (+) m/z 277.0 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1)=[O:18]
Reactant: N#CC1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#CC1CCN(C(=O)CCl)CC1
Temperature: -10 °C
Yield: 92.9 %

Procedure:
A mixture of 4-piperidinecarbonitrile (200 g, 1.80 mol) and 40% aqueous potassium carbonate solution (342 g, 0.99 mol) in dichloromethane (1 L) was cooled to −10° C., and a solution of chloroacetyl chloride (210 g, 1.86 mol) in dichloromethane (300 mL) was added over about 75 minutes while maintaining the reaction mixture at −10 to 0° C. After the addition was complete, the reaction mixture was separated, the upper aqueous phase was extracted with dichloromethane (2×300 mL), and the combined organic phases were concentrated under reduced pressure to give 312 g of the title compound as a liquid which slowly crystallized on standing. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].Cl[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5](=[O:9])[N:6]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:7]=1[CH3:8]
Reactant: ClCc1cccs1
Reactant: CSc1nc(=O)[nH]c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(=O)n(Cc2cccs2)c(C)c1Cl
Yield: 13.6 %

Procedure:
A suspension of 5-chloro-6-methyl-4-methylthiopyrimidin-2-one (1.768 g), 2-chloromethylthiophene (1.505 g) and potassium carbonate (2.499 g) in dry N,N-dimethylformamide (20 ml) was stirred and heated at ca 90° C. for 30 min. The reaction mixture was evaporated to dryness and the residue was partitioned between ethyl acetate (200 ml) and water (50 ml). The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated to a brown solid. Preparative layer chromatography on silica developing with chloroform-ethanol (20:1, two runs) gave a solid which was crystallised from acetone to give cream crystals of the title pyrimidinone (362 mg) m.p. 173°-176° C.; λmax (EtOH) 231.5 nm (ε 17030), 276 nm (ε 9360), 320 nm (ε 10010).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]2[N:19]=[C:18]([N:20]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22][CH2:21]3)[O:17][C:14]2=[N:15][CH:16]=1>>[C:1]1([C:11]2[CH:12]=[C:13]3[N:19]=[C:18]([N:20]4[CH:26]5[CH2:25][CH2:24][N:23]([CH2:28][CH2:27]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cnc2oc(N3CCN4CCC3CC4)nc2c1
Product: c1ccc(-c2cnc3oc(N4CCN5CCC4CC5)nc3c2)cc1
Yield: 50 %

Procedure:
The title compound was prepared according to the procedure in Example 44 using phenylboronic acid and 4-(6-bromo-oxazolo[5,4-b]pyridin-2-yl)-1,4-diaza-bicyclo[3.2.2]nonane (prepared in Example 23) in 50% yield as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 8.10 (d, 1H, J=2.1 Hz), 7.72 (d, 1H, J=2.1 Hz), 7.57-7.55 (m, 2H), 7.47-7.44 (m, 2H), 7.39-7.36 (m, 1H), 4.58 (br s, 1H), 3.98 (t, 2H, J=5.8 Hz), 3.22-3.14 (m, 4H), 3.11-3.01 (m, 2H), 2.22-2.15 (m, 2H), 1.89-1.82 (m, 2H); MS (Cl) m/z 321.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:1]3[CH2:2][CH2:3][C:4]4([O:11][C:10]5[C:12]6[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=5[S:8][CH2:7]4)=[CH:16][CH:15]=[CH:14][CH:13]=6)[CH2:5][CH2:6]3)=[CH:25][CH:26]=2)[CH:34]=[N:33]1
Reactant: BrCc1ccc(-c2cn[nH]c2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(Cc3ccc(-c4cn[nH]c4)cc3)CC1)O2
Temperature: 70 °C
Reaction time: 16 h
Yield: 2.2 %

Procedure:
To a mixture of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.15 g, 0.5 mmol) in anhydrous acetonitrile (5.0 mL) was added 4-[4-(bromomethyl)phenyl]-1H-pyrazole (0.24 g, 1.0 mmol) followed by potassium carbonate (0.20 g, 1.5 mmol). The reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was filtered to remove all the solids and the solvent removed under vacuum. The crude product was purified by reverse phase HPLC to give the desired product as a purple solid (0.005 g, 2.3%). M.p.=190-192° C.; 400 MHz 1H NMR (CDCl3) δ: 8.1 (d, 1H), 7.9 (s, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 4H), 7.5 (t, 1H), 7.4 (d, 2H), 6.5 (s, 1H), 3.6 (s, 2 h), 2.9 (s, 2 h), 2.8 (d, 2H), 2.5 (t, 2H), 2.1 (d, 2H), 1.9 (t, 2H); LCMS: 458 [M+H].
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:7]=1[CH2:13][CH2:14][C:15]2=[O:17]
Reactant: O=C(O)CCc1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2c(F)cc(F)cc21
Yield: 79.6 %

Procedure:
Thionyl chloride (54.6 g) was added dropwise at 40° C. to a solution of 3-(2,4-di-fluorophenyl)propionic acid (57 g) in methylene chloride (200 ml). After reaction was complete, excess thionyl chloride and the solvent were removed by distillation. The oily residue was added dropwise at 40° C. to a suspension of aluminium chloride (88.5 g) in methylene chloride (200 ml). The reaction mixture was added to dilute hydrochloric acid after 18 hours at 40° C. The aqueous phase was separated off and extracted once with methylene chloride (250 ml). The combined organic phases were freed from the solvent and then distilled in vacuo. 41 g of a colorless solid were obtained (m.p.: 103° C.).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[CH3:27].CN([CH:31]=[O:32])C>C1COCC1>[Br:16][C:17]1[C:18]([CH3:27])=[CH:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][C:22]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(F)(F)F)ccc1Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)cc(C=O)c1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
To a 100 mL round bottom flask were added 2,2,6,6-tetramethylpiperidine (2.8 mL, 16.6 mmol), and 50 mL THF. BuLi (9.5 mL, 15.2 mmol, 1.6 M hexane solution) was added via a syringe at 0° C. After stirring at 0° C. for 15 mins, ice bath was replaced with dry ice/ether bath. To another 25 mL round bottom flask was added 1-bromo-2-methyl-4-(trifluoromethyl)benzene (3.3 g, 13.8 mmol) and THF. After cooling with dry ice/acetone bath, this solution was cannular transferred to the first flask rapidly. Upon completion of transferring, DMF (2.1 mL, 27.6 mmol) was added immediately and the resulting reaction mixture was stirred at that temperature for 10 more minutes before it was allowed to warm to −20° C. slowly. The reaction was quenched at −20° C. with addition of 50 mL 1N HCl. This mixture was diluted with 100 mL water and extracted with 100 mL EtOAc/hexane 1:9. The organics were washed with 30 mL NaHCO3 aqueous solution, dried over sodium sulfate, filtered and concentrated. Crude product was purified by chromatography to give 1.8 g 2-bromo-3-methyl-5-(trifluoromethyl)benzaldehyde. 1H NMR (500 MHz, CDCl3) δ10.50 (s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 2.60 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH2:26][S:27][C:28]1[S:32][C:31]([NH2:33])=[N:30][CH:29]=1)[CH3:22]>>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH2:26][S:27][C:28]1[S:32][C:31]([NH:33][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:30][CH:29]=1)[CH3:22]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Product: CCOC(=O)CCSc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
(R)-3-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester was prepared from (R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid and 3-(2-aminothiazol-5-ylsulfanyl)-propionic acid ethyl ester as described in Example 1. 1H_NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.40 (s, 1H), 4.08 (q, 2H), 3.96 (t, 1H), 3.09 (s, 3H), 2.92 (t, 2H), 2.57 (t, 2H), 2.21 (m, 1H), 1.88-1.48 (m, 8H), 1.22-1.17 (m, 5H); HPLC-MS: m/z: 511 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]2[O:7][C:8]([CH3:24])([CH3:23])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH2:19][OH:20])=[CH:13][C:12]3=[O:22])[C:5]=2[CH:4]=1)#[N:2].C(N(CC)CC)C.[Si:34](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].P([O-])([O-])([O-])=O>C(Cl)Cl>[C:1]([C:3]1[CH:26]=[CH:25][C:6]2[O:7][C:8]([CH3:23])([CH3:24])[CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14]([CH:17]([OH:21])[CH2:18][CH2:19][O:20][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])=[CH:13][C:12]3=[O:22])[C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(C)C=C(n2ccc(C(O)CCO)cc2=O)c2cc(C#N)ccc2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C=C(n2ccc(C(O)CCO[Si](C)(C)C(C)(C)C)cc2=O)c2cc(C#N)ccc2O1
Yield: 104 %

Procedure:
In 15 ml of anhydrous methylene chloride, is dissolved 1.06 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1,3-dihydroxypropyl)-1-pyridinyl}-2H-benzo[b]pyran obtained in Example 37. Thereto are added 0.46 ml of triethylamine and 6 ml of a solution containing 0.48 g t-butyldimethylsilyl chloride in anhydrous methylene chloride at 0° C., and the resulting mixture is reacted at room temperature for 8 hours. After stopping the reaction by adding 0.2M phosphate buffer, the reaction mixture is extracted with methylene chloride. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off and the filtrate is concentrated under reduced pressure. Thus, 1.46 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-3-t-butyldimethylsilyloxypropyl)-1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([O:33]C)=[O:32])[C:6]=2[CH:35]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([OH:33])=[O:32])[C:6]=2[CH:35]=1
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a suspension of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in ethanol (20 ml) is added 5N aqueous sodium hydroxide solution (4 ml), and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction solution, and the mixture is made weak acidic with diluted hydrochloric acid, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether, and further recrystallized from diethyl ether to give 7-chloro-5-carboxymethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) as white powder.
Reaction SMILES: C([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[O:23][CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(Cl)(Cl)Cl>[CH2:29]([O:28][C:26]([N:8]1[CH2:22][CH2:21][C:20]2[C:11](=[N:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:19]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)Cl
Reactant: COc1c2c(nc3ccccc13)CCN(Cc1ccccc1)CC2
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2nc3ccccc3c(OC)c2CC1
Reaction time: 24 h

Procedure:
A mixture of 3.7 gm (11.6 millimols) of 3-benzyl-11-methoxy-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline, 1.1 ml (11.6millimols) of ethyl chloroformate and 35 ml of chloroform was stirred at 5° for 24 hours. After evaporation, the residue was chromatographed on silicagel with toluene/acetone (8:1) as the eluant.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([OH:13])[CH:9]=[CH:8][CH:7]=2.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[C:3]([OH:2])[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cc2cccc(O)c2cc1O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1cc2cccc(OCc3ccccc3)c2cc1O
Yield: 7 %

Procedure:
To a stirred solution of 7.8 g (0.34 g atom) of sodium in 1,000 cc of ethanol, was added 85 g (0.37 mole) of ethyl 3,5-dihydroxy-2-naphthoate. After one-half hour 47 g (0.37 mole) of benzyl chloride was added. The reaction mixture was warmed under reflux for 24 hours. The hot reaction mixture was filtered and cooled in an ice bath. A tan solid precipitated out, which was filtered off yielding 15.0 g (m.p. 98°-115° C.) of the crude product. Recrystallization first from ethanol and then from acetonitrile furnished ethyl 5-benzyloxy-3-hydroxy-2-naphthoate, m.p. 112° C.-114° C. in 7 percent yield (7.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].Cl.[CH3:29][NH2:30]>>[CH3:29][NH:30][C:24]([C:21]1[O:22][C:23]2[C:15]([N:12]3[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:10][CH2:11]3)=[CH:16][CH:17]=[CH:18][C:19]=2[CH:20]=1)=[O:25]
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: CN
Agent: Cl
Agent: [Li+]
Product: CNC(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and methylamine hydrochloride (90 mg, 1.3 mmol). Yield: 50 mg (62%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[C:16]([O:19][CH3:20])[C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH2:24][CH3:25])[N:17]=[C:16]([O:19][CH3:20])[C:15]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: COc1n[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc(OC)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.83 h

Procedure:
A solution of 30 mg (0.10 mmol) of 1-tert-butoxycarbonyl-4-(3-methoxy-4-methyl-(1H)-pyrazol-5-yl)piperidine (from Step D) in 1 mL of DMF at 0° C. was treated with 3.5 mg (0.15 mmol) of 95% NaH and 0.012 mL (0.15 mmol) of ethyliodide. After 50 minutes, the reaction was partitioned between 25 mL of EtOAc and 25 mL of brine. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 99:1 v/v CH2Cl2/acetone, 98:2 v/v CH2Cl2/acetone and 97:3 v/v CH2Cl2/acetone as the gradient to afford the title compound: RF: 0.39 (19:1 v/v CH2Cl2/acetone); 1H-NMR (500 MHz) δ 1.33 (t, J=7.1, 3H), 1.49 (s, 9H), 1.69–1.72 (m, 2H), 1.82–1.90 (m, 2H), 1.91 (s, 3H), 2.68–2.74 (m, 3H), 3.88 (s, 3H), 3.98 (q, J=7.1, 2H), 4.25 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)[C:7]([OH:9])=[O:8])([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]1[O:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:16][N:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccc(C(F)(F)F)cc3)o2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(C(=O)O)ccc1-c1nnc(-c2ccc(C(F)(F)F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
A mixture of 3-nitro-4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.600 g), 5% palladium on carbon (0.600 g) and tetrahydrofuran (15 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1, volume ratio) to give 3-amino-4-[5-(4-trifluoromethylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (0.33 g, yield 59%). Recrystallization from hexane-tetrahydrofuran gave yellow prism crystals. melting point: >300° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([Sn](C)(C)C)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19].Br[C:21]1[C:22]([CH3:38])=[N:23][C:24]([C:27]2[N:31]=[CH:30][N:29](C3CCCCO3)[N:28]=2)=[CH:25][CH:26]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]2=[N:11][C:12]([C:21]3[C:22]([CH3:38])=[N:23][C:24]([C:27]4[NH:31][CH:30]=[N:29][N:28]=4)=[CH:25][CH:26]=3)=[CH:13][N:14]=[C:9]2[NH:8][CH2:7][C:6]1=[O:19]
Reactant: Cc1nc(-c2ncn(C3CCCCO3)n2)ccc1Br
Reactant: COCCN1C(=O)CNc2ncc([Sn](C)(C)C)nc21
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1C(=O)CNc2ncc(-c3ccc(-c4nnc[nH]4)nc3C)nc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
1-(2-Methoxyethyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.5 g, 1.348 mmol), 3-bromo-2-methyl-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (0.436 g, 1.348 mmol), tris(dibenzylidineacetone)dipalladium(0) (0.123 g, 0.135 mmol), tri-o-tolylphosphine (0.082 g, 0.270 mmol), triethylamine (0.584 mL, 4.04 mmol) and N,N-dimethylformamide (10 mL) were combined in a 75 mL sealable flask, the atmosphere in the flask was removed and replaced with nitrogen. The mixture was stirred at 130° C. for 3 h. The resulting mixture was cooled to room temperature and filtered. The organic layer was concentrated under reduced pressure. The resulting residue was diluted with methanol and dimethylsulfoxide, filtered and purified using reverse-phase preparatory HPLC (10-30% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing clean product were passed through a Phenomenex Strata-X—C solid phase extraction column. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure. The residue was triturated with ethyl ether in hexane to make a fine powder and dried under vacuum at 50° C. to give the desired product (0.05 g, 0.136 mmol, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.10 (br. s., 1H), 7.98 (br. s., 1H), 7.94 (s, 1H), 7.73 (br. s., 1H), 4.13-4.28 (m, 4H), 3.55 (t, J=6.25 Hz, 2H), 3.24 (s, 3H), 2.70 (br. s., 3H); MS (ESI) m/z 367.2[M+1]+.