Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)=[O:4].[C:15]([OH:18])(=[O:17])C>[C].[Rh]>[C:5]([O:18][C:15]([N:7]1[CH2:6][C@@H:5]([C:3]([OH:2])=[O:4])[CH2:10][C@@H:9]([C:11]([OH:13])=[O:12])[CH2:8]1)=[O:17])([CH3:6])([CH3:10])[CH3:3]
Reactant: CC(=O)O
Reactant: COC(=O)c1cncc(C(=O)OC)c1
Agent: [Rh]
Product: CC(C)(C)OC(=O)N1C[C@H](C(=O)O)C[C@H](C(=O)O)C1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
Dimethylpyridine-3,5-dicarboxylate (62.8 g) was dissolved in acetic acid (300 mL), 5% rhodium-carbon (6 g) was added and the mixture was stirred under hydrogen pressurization (5 atm) at 50° C. for 20 hr. The reaction mixture was allowed to cool to room temperature, the rhodium catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (300 mL), and triethylamine (180 mL) and di-tert-butyl bicarbonate (105 g) were successively added under ice-cooling. The reaction mixture was stirred at room temperature for 15 hr, and concentrated under reduced pressure. The residue was dissolved in water, and the mixture was adjusted to pH 3 with 6M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extraction layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (300 mL), and 8N aqueous sodium hydroxide solution (161 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 20 hr, and methanol was evaporated under reduced pressure. The concentrate was diluted with saturated aqueous sodium hydrogen carbonate solution (100 ml) and washed twice with diethyl ether. The basic aqueous layer was acidified (pH 3) with 6M hydrochloric acid. The precipitated powder was collected by filtration, washed with water and air-dried to give the object product (80.5 g) as a powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: CC(=O)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1)c1ccccc1
Temperature: 110 °C
Yield: 47.8 %

Procedure:
To a degassed solution of 4-benzyl-2-(4-bromo-phenyl)-morpholine (205 mg; 0.62 mmol) and acetophenone (87 μL; 0.74 mmol) in toluene (4 mL) was added NaOtBu (148.3 mg; 1.54 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (38.4 mg; 0.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (28.3 mg; 0.03 mmol). The resulting mixture was heated to 110° C. for 30 min. in a microwave. After cooling to room temperature 5% aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 2-[4-(4-Benzyl-morpholin-2-yl)-phenyl]-1-phenyl-ethanone (110.00 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[C:29](=[O:30])[CH2:28][C@@H:27]6[NH:31][C@@H:24]([CH2:25][CH2:26]6)[CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].C(N(C(C)C)CC)(C)C.C(Cl)Cl>CCOC(C)=O>[C:37]([N:31]1[C@@H:27]2[CH2:26][CH2:25][C@H:24]1[CH2:23][N:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[N:17][CH:18]=1)[C:29](=[O:30])[CH2:28]2)(=[O:39])[CH3:38]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CC[C@H](CC4=O)N5)cn3)nc2n1C1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1[C@@H]2CC[C@H]1CN(c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc1)C(=O)C2
Reaction time: 16 h
Yield: 59.1 %

Procedure:
A sample of 7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.102 mmol), acetic anhydride (0.020 ml, 0.113 mmol) and diisopropylethylamine (0.014 ml, 0.154 mmol) were combined with 1 ml DCM. The mixture was allowed to stir for 16 hr and then taken up into EtOAc, washed with brine, dried over Na2SO4 filtered and concentrated. The crude product was purified by silica gel chromatography which gave 2-(5-((1S,6R)-9-acetyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (32 mg) 52% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (d, J=8.08 Hz, 1H), 8.82 (s, 1H), 8.33 (dd, J=9.09, 6.06 Hz, 1H), 8.13 (d, J=2.53 Hz, 1H), 7.60 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (t, J=8.84 Hz, 1H), 4.70 (br. s., 0H), 4.55 (m, 0H), 4.43 (s, 0H), 4.34 (br. s., 0H), 4.18 (d, J=14.65 Hz, 0H), 4.06 (d, J=14.15 Hz, 0H), 3.59 (m, 1H), 3.06 (br. s., 6H), 2.98 (d, J=16.17 Hz, 1H), 2.87 (d, J=14.65 Hz, 0H), 2.73 (m, 1H), 2.44 (br. s., 2H), 2.19 (m, 1H), 2.05 (d, J=4.55 Hz, 3H), 1.98 (m, 6H), 1.82 (m, 2H), 1.66 (d, J=5.56 Hz, 3H), 1.23 (br. s., 1H). MS m/z 531.6 (M+H).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17](Cl)[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:27])=[CH:6][C:7]([F:26])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([NH:2][CH3:1])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Solvent: c1ccncc1
Product: CNc1nc2c(cc1F)c(=O)c(C(=O)O)cn2-c1cc(N)c(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (150 mg) of methylamine and 1-(5-amino-2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (150 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ethanol was added to the residue, and solids deposited were collected by filtration to obtain the title compound (40 mg) as colorless crystals.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=O)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH2:30][N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CN1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
To a solution of 264 (300 mg, 0.66 mmol), N-methylpiperazine (74 μl, 0.66 mmol) and AcOH (76 μl, 1.33 mmol) in NMP (10 mL) was added sodium triacetoxyborohydride (422 mg, 1.99 mmol) and the reaction mixture was stirred for 2.5 days at RT. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic extract was successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15μ, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:20/80 to 95/5 over 60 min, flow; 30 mL/min) to afford the title compound 266 (180 mg, 0.33 mmol, 51% yield, di-formate salt) as a white solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=[C:22]2[CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([CH2:20][N:21]2[C:25]([C:26]([NH2:28])=[O:27])=[C:24]([CH:29]([OH:33])[CH2:30][CH2:31][CH3:32])[N:23]=[C:22]2[CH2:34][CH2:35][CH3:36])=[CH:18][CH:19]=1)([OH:7])=[O:5]
Reactant: CCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 45(d), but using a solution of 0.82 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2-propylimidazole-5-carboxamide [prepared as described in step (c) above] in 17 ml of a 4N solution of hydrogen chloride in dioxane, 0.78 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at 118°-121° C. (with softening).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:26][CH3:27])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([O:11]CC(OC)OC)=[O:10].[OH-].[Na+].Cl>CO>[CH3:27][O:26][CH:3]([O:2][CH3:1])[CH2:4][O:5][C:6]1[C:7]([CH3:25])=[C:8]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[C:9]([OH:11])=[O:10]
Reactant: COC(COC(=O)c1ccc(S(C)(=O)=O)c(OCC(OC)OC)c1C)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(COc1c(S(C)(=O)=O)ccc(C(=O)O)c1C)OC
Reaction time: 0.5 h

Procedure:
The 2,2-dimethoxyethyl 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoate obtained in the above step (1) was dissolved in methanol (20 mL), and an aqueous sodium hydroxide solution (2 mL) at a concentration of 20 wt % was added thereto at room temperature. After stirring for 30 minutes, 100 mL of 1N hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate (200 mL). The organic layer was washed twice with a saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3-(2,2-dimethoxyethoxy)-2-methyl-4-(methylsulfonyl)benzoic acid (390 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[Cl:11][C:12]([Cl:16])=[C:13]([F:15])[F:14].C(N(CC)CC)C>O>[Cl:11][C:12]1([Cl:16])[CH:7]([C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:8][C:13]1([F:15])[F:14]
Reactant: FC(F)=C(Cl)Cl
Reactant: C=Cc1ccc(OC)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2CC(F)(F)C2(Cl)Cl)cc1

Procedure:
p-Methoxystyrene (40.8 g., 0.30 mole), 1,1-dichloro-2,2-difluoroethylene (55.8 g., 0.42 mole), and triethylamine (3.0 ml., 0.02 mole) are heated in a sealed tube (25 × 615 mm) at 125°-130°C. for 16 hrs. The cooled mixture is then poured into water, the reaction product extracted with ether, and the extracts washed with water, dried (MgSO4), and evaporated to an oil. Distillation of the oil yields 69.0 g. (86%), b.p. 80°-85°C. (0.1 mm), of the desired intermediate suitable for use in the next step. Part of the oil was chromatographed (alumina, cyclohexane), and redistilled, b.p. 81°C. (0.02 mm), nD27 1.5207.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:23][OH:24]>C(O)(C)C>[OH:24][NH:23][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(NO)nc3ccccc23)cc1
Temperature: 130 °C
Yield: 40.5 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and hydroxylamine hydrochloride (6.7 mg, 0.10 mmol) in isopropanol was heated by microwave at 130° C. for 20 min. The solvent was evaporated under reduced pressure. The product was isolated by preparative TLC as white solid (6 mg, 40%) using acetone:hexane (1:1) as eluent. 1H NMR (CDCl3): 7.65 (d, J=8.4 Hz, 1H), 7.47 (ddd, J=8.4, 6.9 and 1.8 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.88-6.75 (m, 2H), 3.86 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].I[CH3:16].O>CN(C=O)C>[I:14][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:3][CH3:16])[CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(I)cc1OC
Reaction time: 2 h

Procedure:
238 mg (7.9 mmol) of sodium hydride (80% in oil) and 20 ml of DMF were introduced into a three-necked flask, a solution of 2 g (7.2 mmol) of methyl 2-hydroxy-4-iodobenzoate in 50 ml of DMF was added dropwise and stirring was carried out until gas evolution had ceased. 540 μl (8.6 mmol) of iodomethane were then added and stirring was carried out at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 2.1 g (100%) of methyl 4-iodo-2-methoxybenzoate were recovered.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:12])=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[C:7]([CH3:12])=[CH:8][N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: Cc1cnc(Cl)c2ncc(Br)n12
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)CO
Product: Cc1cnc(NCc2ccc(S(N)(=O)=O)cc2)c2ncc(Br)n12
Temperature: 108 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of 3-bromo-8-chloro-5-methyl-imidazo[1,2-a]pyrazine (308 mg, 1.25 mmol) in iBuOH (5 mL) is added 4-aminomethyl-benzenesulfonamide hydrochloride (298 mg, 1.38 mmol) and DIPEA (0.43 mL, 3.12 mmol). The reaction is stirred at 108° C. for 16 h. After this time the solution is allowed to cool, resulting in a thick precipitate that is filtered and washed with diethyl ether to give 330 mg of pure product as a beige solid (67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][C:8](=O)[C:7]=2[CH:12]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:20][C:21](=[O:23])[CH3:22])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:20][C:21]([CH3:22])=[O:23])[C:7]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CO2
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2occ(CC(C)=O)c2c1

Procedure:
A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1-triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1-(5-methoxy-1-benzofuran-3-yl)acetone was obtained as a red oil. Yield: 1.1 g (53%); 205 (M+H).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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.[CH2:21]([NH:23][CH2:24][CH2:25][NH2:26])[CH3:22]>CCOC(C)=O.CO>[C:1]([NH:26][CH2:25][CH2:24][NH:23][CH2:21][CH3:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH: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
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNCCN
Solvent: CCOC(C)=O
Solvent: CO
Product: CCNCCNC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Trityl chloride (˜3.45 g, ˜12.5 mmol) was slowly added into N-ethylethlenediamine (˜1.1 g, ˜12.5 mmol) DCM (methylene chloride) solution with stirring. After the reaction mixture was stirred at room temperature overnight (˜23 hours), HPLC indicated that the reaction was complete. After Biotage silica gel chromatography was performed (EtOAc/MeOH), Compound 2 was obtained as a white solid (˜3.5 g, ˜85% isolated yield), and the product was confirmed by proton NMR.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:13][CH:12]=1)C.N>O1CCCC1>[N:20]1([CH2:19][CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([CH2:10][OH:9])=[CH:16][CH:15]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(OCCN2CCCCC2)cc1
Yield: 82.5 %

Procedure:
To a suspension of lithium aluminum hydride (1.5 g) in tetrahydrofuran (50 ml) under a nitrogen atmosphere was added 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (5.0 g) on an ice bath, and the solution was refluxed for 1 hour. Ammonia solution was added thereto on an ice bath, the solution was filtered through celite pad, then the solvent was evaporated in vacuo, and [4-(2-piperidin-1-ylethoxy)phenyl]methanol (3.5 g) was obtained. To a solution of this compound (1.7 g) in chloroform (30 ml) was added manganese(IV) oxide (7.5 g), the solution was stirred overnight at room temperature, then filtered, and the solvent was evaporated in vacuo to provide the title compound (1.7 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl>[CH2:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:10][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:12][CH2:13]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1.14 ml (10.5 mmol) of phenyl isocyanate are slowly added dropwise to a solution of 1.90 g (10.0 mmol) of 4-amino-1-benzylpiperidine and 1.46 ml (10.5 mmol) of triethylamine in 40 ml of dichloromethane. The reaction mixture may subsequently be stirred at room temperature for 1 h, and is then evaporated to dryness in vacuo. The residue is mixed with 50 ml of diethyl ether, stirred well, separated off by filtration, washed with 5 ml of diethyl ether and dried in a high vacuum. 2.62 g (85%) of the title compound are obtained as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:1][C:2]1[C:11]([NH:14][NH2:15])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NN
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: CCO
Solvent: O
Product: NNc1nc2ccccc2nc1Cl
Yield: 41 %

Procedure:
2,3-Dichloroquinoxaline (33.5 g., 0.168 mole) was stirred with hydrazine hydrate (18.5 g., 0.369 mole) in 500 ml. of ethanol at room temperature overnight (i.e.. at ca. 20° C. for approximately 16 hours). The thick, yellow slurry was filtered and the precipitate was washed with ethanol. The precipitated material was recrystallized from hot methanol to give 13.5 g. (41% yield) of 2-chloro-3-hydrazinoquinoxaline, m.p. 181° C. (decomp.). Mass spectrum: m/e, 194 (P).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: Br
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
The mixture of 3.0 g of 2-(p-methoxyphenyl)-pyrazolo-[4,3-c]quinolin-3(5H)-one and 260 ml of 48% hydrobromic acid is refluxed for 1 hour and concentrated to about 50 ml. The concentrate is cooled to room temperature, the precipitate collected, washed with methanol and diethyl ether, and dissolved in diluted aqueous sodium hydroxide. The solution is washed with diethyl ether, then its pH adjusted to 8.5 by addition of ammonium chloride, precipitating a solid which is collected, washed with methanol, then with diethyl ether and dried, to yield the 2-(p-hydroxyphenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one melting at 294°-296°.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1[CH:16]=[CH:15][C:6](/[CH:7]=[N:8]/[S@@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[C:5]([F:17])[CH:4]=1.[CH3:19][Mg]Br>C(Cl)Cl>[F:18][CH:2]([F:1])[C:3]1[CH:16]=[CH:15][C:6]([C@@H:7]([NH:8][S@@:9]([C:11]([CH3:13])([CH3:14])[CH3:12])=[O:10])[CH3:19])=[C:5]([F:17])[CH:4]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccc(C(F)F)cc1F
Solvent: ClCCl
Product: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(F)F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R,E)-N-(4-(difluoromethyl)-2-fluorobenzylidene)-2-methylpropane-2-sulfinamide (266 mg, 0.959 mmol) in DCM (9.6 mL) was added methylmagnesium bromide (3M in diethylether; 1.20 mL) at 0° C. The reaction mixture was allowed to stir for 30 min at 0° C., gradually allowed to warm to room temperature and stirred for 1 hour at room temperature. The mixture was cooled to 0° C., and carefully quenched with saturated aqueous NH4Cl solution (3 mL). The separated aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate], providing (R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (160.5 mg) as a white solid. LCMS m/z 294.5 (M+H)+, Rt 0.85 min.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:28])[C:7]([CH3:27])=[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][O:20]C3CCCCO3)[O:9]2)=[CH:4][CH:3]=1.CO.[ClH:31]>O>[ClH:31].[OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:28])[C:7]([CH3:27])=[C:8]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:18][CH2:19][OH:20])[O:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c([C@H]2CCCN2CCOC2CCCCO2)oc2c(C)c(O)ccc2c1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1c([C@H]2CCCN2CCO)oc2c(C)c(O)ccc2c1=O
Temperature: 55 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
A mixture composed of 7-hydroxy-3,8-dimethyl-2-{(2R)-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrrolidin-2-yl}-4H-chromen-4-one (77 mg, 0.20 mmol) obtained in Example 4-1, methanol (6 mL), concentrated hydrochloric acid (0.5 mL), and water (1 mL) was heated with stirring at a bath temperature of 55° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse-phase HPLC. A 1 N aqueous hydrochloric acid solution (4 mL) was added to a fraction containing the compound of interest, and then the mixture was concentrated under reduced pressure. Diethyl ether and methanol were added to the obtained residue, and the mixture was powdered. The obtained solid was collected by filtration and then dried in a vacuum pump to obtain 40 mg of the title compound (yield: 53%).