Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Br[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]2=[O:37])=[N:28][CH:29]=1>CN(C=O)C>[Cl:36][C:34]1[CH:33]=[CH:32][C:31](=[O:37])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][O:7][C:8]3[CH:15]=[C:14]([CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)[CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[CH:29][N:28]=2)[CH:35]=1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-n2cc(Cl)ccc2=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (0.123 g, 0.376 mmol) was added to a solution of 2-hydroxy-4-imidazol-1-ylmethyl-benzonitrile (as described in Example 4, Step F) (0.050 g, 0.25 mmol) and 5′-bromomethyl-5-chloro-[1,2′]bipyridinyl-2-one (Step H) (0.079 g, 0.263 mmol) in anhydrous DMF (5 mL) and stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and aqueous saturated NaHCO3 solution, the organic layer separated, washed with H2O, brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (silica gel, 1-4% CH3OH/CH2Cl2). FAB MS 418 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:31][C:2]1([CH3:1])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]([N:25]3[CH2:26][CH2:27][N:28]([CH2:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=4)[CH2:29][CH2:30]3)[C:12]3[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[C:4]=2[O:3]1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCNCC2)cc1
Reactant: O=Cc1ccccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3c2OC(C)(C)C3)N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 1883 %

Procedure:
The title compound 9 was prepared by dissolving compound 5 (0.45 g, 0.98 mmol) in MeOH (10 mL) with 2-pyridine carboxaldehyde (110 μL, 1.18 mmol) and HOAc (3 μL, 50 μmol). Sodium cyanoborohydride (70 mg, 1.18 mmol) was added at 0° C. and reaction stirred 48 h at 25° C. Reaction was worked up by concentration in vacuo, extraction (CH2Cl2/K2CO3(aq)) and chromatography by reverse phase HPLC to give the title compound 9,461 mg(63%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.S(Cl)([Cl:12])=O>>[CH3:1][N:2]1[C:6]([C:7]([Cl:12])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cn1nccc1C(=O)Cl
Yield: 51 %

Procedure:
To a stirred solution of 1-methyl-1H-pyrazole (77.0 g 0.916 mol) in absolute ether (960 mL) under an atmosphere of argon was added a 1.6 M solution of n-BuLi in hexane (600 mL, 0.96 mol) dropwise at −40° C. over a period of 2 h. The reaction mixture was stirred at this temperature for a further 1 h, then siphoned into a mixture of solid carbon dioxide with ether. After heating to room temperature, the resulting mass was treated with water (1.5 L), the aqueous layer was separated, washed with ether (500 mL), concentrated to half volume under reduced pressure on a rotary evaporator, cooled to 2–3° C., and acidified while stirring with concentrated HCl to pH=3. The resulting precipitate was separated by filtration, washed with ice-cold water (25 mL), dried first in open air, and then in a vacuum desiccator over P2O5 to give 86.5 g (76%) of 1-methyl-1H-pyrazole-5-carboxylic acid as a white powder. To thionyl chloride (650 mL) was added 1-methyl-1H-pyrazole-5-carboxylic acid (86.5 g, 0.67 mol) in portions over a 35 min period, such that each portion was consumed before addition of the next. After this, the reaction mixture was refluxed for 4.5 h. The excess thionyl chloride was removed under vacuum at a bath temperature below 35° C. The residue was subjected to vacuum fractional distillation through a 15-cm Vigreux column. A fraction boiling at 71–72° C. at 15–16 mm Hg was collected to obtain the title product (49.0 g, 51%) as a colorless liquid.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH3:11])=[N:9][N:10]=[C:6]2[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[SH-:17].[Na+].Cl>O>[CH2:15]([O:14][C:12]([C:4]1[CH:3]=[C:2]([SH:17])[N:7]2[C:8]([CH3:11])=[N:9][N:10]=[C:6]2[N:5]=1)=[O:13])[CH3:16]
Reactant: [SH-]
Reactant: CCOC(=O)c1cc(Cl)n2c(C)nnc2n1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2c(C)nnc2n1
Yield: 80.8 %

Procedure:
The product obtained in Step 2 (4.0 g) was added at a time under ice cooling to a solution of 4.0 g of sodium hydrosulfide in 100 ml of water with stirring in nitrogen, and the mixture was stirred at room temperature overnight. The resulting solution was acidified to pH 1.0 with 6N hydrochloric acid, and the separated crystals were collected by filtration and recrystallized from ethanol, affording 3.2 g of the objective compound as orange crystals.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][NH:15]2)=[CH:11][CH:10]=1.I[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH:18]=[O:19])=[CH:14][N:15]2[CH:21]([CH3:23])[CH3:22])=[CH:11][CH:10]=1
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C=O)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Cesium carbonate (558 mg, 1.71 mmol) was added to a stirred room temperature of 6-methoxy-1H-indole-3-carbaldehyde (100 mg, 0.57 mmol) in DMF (1.0 mL) and the mixture was stirred at room temperature for 15 minutes. Then 2-iodopropane (0.114 mL, 1.14 mmol) was added and the solution was stirred for 80° C. for 2 hours. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (2×15 mL) and saturated sodium bicarbonate (5 mL), washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title intermediate (108 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1.CCO>[Ni].C1COCC1>[CH3:37][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]2[N:18]=[CH:19][C:20]3[CH2:21][C:22](=[O:36])[NH:23][C:24]4[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:25]=4[C:26]=3[N:27]=2)[C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1
Reactant: CN(C)CC#Cc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(C)CCCc1cnc(C(F)(F)F)c(Nc2ncc3c(n2)-c2ccc(C(F)(F)F)cc2NC(=O)C3)c1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a round bottom flask were added 2-{[5-[3-(dimethylamino)prop-1-yn-1-yl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.042 g, 0.081 mmol), EtOH (5 mL), THF (1 mL), and Raney nickel (20 mg). The resulting mixture was allowed to stir under a hydrogen balloon overnight. The mixture was filtered through celite and the filtrate was concentrated. The residue was purified by column chromatography to give 2-{[5-[3-(dimethylamino)propyl]-2-(trifluoromethyl)pyridin-3-yl]amino}-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.033g, 78%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@@H:14](O)[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](/[CH:13]=[CH:14]/[C:15]([F:18])([F:16])[F:17])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@@H](O)C(F)(F)F)c1=O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reaction time: 12 h

Procedure:
280 mg (0.74 mmol) of the compound from Example 7A were introduced at RT together with 108.1 mg (0.89 mmol) of 4-dimethylaminopyridine in 5.3 ml of pyridine, admixed with portions of 0.31 ml (1.84 mmol) of trifluoromethanesulphonic anhydride and stirred for 12 h. The pyridine was removed on a rotary evaporator and the residue was taken up in acetonitrile and 1N hydrochloric acid. The product was purified by preparative HPLC (Method 10). This gave 230 mg (86% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:24]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
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: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), phenylboronic acid (11.1 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.10 (d, J=6.8 Hz, 3H), 6.55 (q, J=6.6 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 7.48-7.56 (m, 3H), 7.59 (d, J=2.3 Hz, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.80-7.85 (m, 2H), 8.05 (s, 1H), 8.21 (d, J=9.6 Hz, 1H). MS (ES+): m/z 373.09 (100) [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:19][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:18][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1OCc1ccccc1[N+](=O)[O-]

Procedure:
75 g (0.347 mol) of 2-nitrobenzyl bromide, 37 g (0.342 mol) of o-cresol and 56 g (0.405 mol) of potassium carbonate in 500 ml of dimethylformamide is stirred for 5 hours at room temperature (20° C.). The reaction mixture is diluted with water and the aqueous phase is extracted three times with ether. The ether phase is dried and evaporated down. The crystalline residue is stirred with methanol and suction filtered. There is obtained 73 g (0.300 mol=88%) of the title compound as a colorless solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:17]2=O)=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[Cl:5][C:6]1[N:7]=[C:8]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C@H:17]2[NH:4][CH:1]([CH3:3])[CH3:2])=[O:14])[NH:9][C:10]=1[CH2:11][CH3:12]
Reactant: CCc1[nH]c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2=O)nc1Cl
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(C)C)nc1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
Isopropylamine (372 μL, 4.37 mmol) was added to a solution of tert-butyl 4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-oxopiperidine-1-carboxylate obtained in Example (201c) (162 mg, 0.437 mmol) in tetrahydrofuran (4 mL), and the mixture was heated under reflux at 50° C. for four hours. The reaction solution was concentrated under reduced pressure, and then tetrahydrofuran (3 mL) and methanol (3 mL) were added. Isopropylamine (37.2 μL, 0.437 mmol), sodium cyanoborohydride (82.4 mg, 1.31 mmol) and acetic acid (150 μL, 2.62 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to the residue, followed by extraction with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, and then the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography and preparative TLC (eluent: chloroform:methanol=10:1 v/v) to obtain 24 mg of the cis isomer of the title compound (15%) as a pale yellow oily substance and 20 mg of the trans isomer of the title compound (12%) as a pale yellow oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cncc(-c3ccc(C(F)(F)F)cc3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A solution of 39 mg (0.17 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 3-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 33 mg (41%) of the title compound as light brown powder.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.Cl[CH2:18][C:19](=[O:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:18][C:19](=[O:21])[CH3:20])[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.5 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (822 mg, 3.42 mmol), chloroacetone (0.429 ml, 5.12 mmol) in DMF (10 ml) was added K2CO3 (1.42 g, 10.3 mmol) and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water and saturated aqueous NaCl, dried and concentrated in vacuo to give a crude solid. The crude residue was triturated with hexane/ethyl acetate (3:1), collected by filtration, rinsed with hexane/ethyl acetate (3:1) and dried to afford 2-chloro-5-(2-oxopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (737 mg, 2.48 mmol, 73% yield) as a pale brown solid. MS [M+H] found 297.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[C:19]#[N:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[C:19]#[N:20])[N:10]=2
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc(N)cn3)c2)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(N)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
Potassium thiocyanate (536 mg, 5.52 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-cyanophenyl}-3-(1-cyano-1-methylethyl)benzamide (550 mg, 1.38 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (242 mg, 1.51 mmol) in acetic acid (7 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100). The obtained solution was concentrated under reduced pressure to give the title compound (0.51 g, 81%) as a pale-yellow amorphous substance.
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH3:6].C(O)C.Cl>O1CCCC1>[OH:3][C@H:4]([C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C@@H:5]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH3:6]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCN[C@@H](C)[C@H](O)c3ccc(O)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](NCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1)[C@H](O)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.43 mL) was added to a solution of ethyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}biphenyl-4-carboxylate (0.15 g), ethanol (20 mL) and tetra hydrofuran (5 mL). The mixture was stirred at 60° C. for 16 hrs, and heated under reflux at 100° C. for 7.5 hrs. A 2 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added, and heated under reflux for 16 hrs. After being cooled to room temperature, 2 mol/L hydrochloric acid (0.60 mL) was added, and the precipitate was collected by filtration to afford the title compound as a pale yellow amorphous (0.13 g). The structure and physical data were shown in table 3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]>C(#N)C>[CH3:7][O:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: COC(=O)c1cnc(Br)c(-c2ccc(F)cc2)n1
Reactant: C1CCNCC1
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCCCC2)c(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Piperidine (0.48 ml, 4.82 mmol, 2.0 eq) was added portion-wise to a acetonitrile (2 ml) solution of 5-bromo-6-(4-fluoro-phenyl)-pyrazine-2-carboxylic acid methyl ester (0.75 g, 2.41 mmol, 1.0 eq) at room temperature. The mixture was irradiated at 100° C. in a microwave with stirring for 30 minutes. HPLC-MS indicated complete consumption of starting material. The crude mixture was cooled to room temperature concentrated. The residue was re-dissolved in ethyl acetate (10 ml), washed with water (5 ml) and the organic phase dried over MgSO4. Following filtration and evaporation in vacuo, the residue was purified by chromatography on silica gel using a gradient of heptane to 10% ethyl acetate in heptane to afford 6-(4-fluoro-phenyl)-5-piperidin-1-yl-pyrazine-2-carboxylic acid methyl ester. Yield=0.48 g (63%). 1H NMR (250 MHz, CDCl3): δ 1.42-1.53 (6H, m), 3.20-3.24 (4H, m), 3.88 (3H, s), 7.06 (2H, t, J=8.78 Hz), 7.74-7.80 (2H, m), 8.68 (1H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([C:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(O)[C:22]#[CH:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([C:21]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]=2[CH:23]=[CH:22]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(ccc4ccccc34)O2)cc1
Reaction time: 1.5 h
Yield: 66 %

Procedure:
A mixture of 2-naphthol (3.23 g;0.0224 mol), 1,1-dianisylprop-2-yn-1-ol (6.00 g;0.0224 mol), acidic alumina Brockmann 1(6 g) and toluene (250 ml) was heated and stirred for 1.5 h, cooled, filtered and the solid washed with toluene. The filtrate was evaporated to give a pale purple tacky solid which was washed with pet. ether (40-60)/diethyl ether to yield crude product (7.07 g). Purification of the solid by crystallisation from ethylacetate gave 3,3-dianisyl-3H-naphtho[2,1-b]pyran as a white solid (5.52 g;66% yield), m.pt 176°-177° C. ##STR10##