Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:29]([Cl:30])=[C:28]([Cl:31])[C:27]([Cl:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Cl:20][C:21]1[C:29]([Cl:30])=[C:28]([Cl:31])[C:27]([Cl:32])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,3,4,5-Tetrachlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,3,4,5-tetrachlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:29])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][C:14]([C:16]3([CH3:29])[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)=[O:15])[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CCNCC1
Yield: 56 %

Procedure:
tert-Butyl 4-(3-(4-fluorophenoxy)phenylcarbamoyl)-4-methylpiperidine-1-carboxylate from step A was treated with 4 N HCl in dioxane for 16 hours at room temperature. The product was isolated by filtration and washed with ether to afford the title compound (206 mg, 56% for two steps) as the hydrochloride salt. MS (ES+) [M+H]+=329.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.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>[CH3:12][Si:13]([C:16]#[C:17][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1)([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A stirred solution at room temperature of methyl 4-bromobenzoate (8.84 g, 41.11 mmol), Pd(PPh3)2Cl2 (840 mg, 1.20 mmol) and Cul (455 mg, 2.39 mmol) in anhydrous THF (200 ml) was saturated with nitrogen for 15 min. Then, the solution under nitrogen was cooled down at 0° C., and trimethylsilylacetylene (7.2 ml, 50.91 mmol) and triethylamine (22 ml, 157.8 mmol) were added successively. The reaction mixture was allowed to warm up at room temperature. After 2 h, Pd(PPh3)2Cl2 (100 mg) and Cul (80 mg) and trimethylsilylacetylene (0.5 ml) were added again, and the reaction mixture was stirred overnight. Then, the reaction mixture was diluted with AcOEt and successively washed with a saturated aqueous solution of NH4Cl and brine, dried over MgSO4, filtered and concentrated. The crude residue was then purified by flash chromatography on silica gel (AcOEt/hexane:5/95□10/90) to afford the title compound XXXI (9.05 g, 38.95 mmol, 94% yield) as a yellow sticky solid. 1H NMR: (400 MHz, CDCl3) δ (ppm): AB system (δA=7.67, δB=7.22, JAB=8.5 Hz, 4H), 3.63 (s, 3H), 0.00 (s, 9H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]3C=C(C(OCC)=O)[N:23]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1)=[O:2].Br[CH2:30][C:31](=O)[C:32]([F:35])([F:34])[F:33]>>[C:15]1([C:14]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=3)=[N:10][C:11]3[N:12]([CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[N:23]=3)[CH:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: O=C(CBr)C(F)(F)F
Product: O=Cc1ccc(-c2nc3nc(C(F)(F)F)cn3cc2-c2ccccc2)cc1

Procedure:
This compound was prepared in a manner according to ethyl 7-(4-formylphenyl)-6-phenylimidazo[1,2-a]pyrimidine-2-carboxylate by using 3-bromo-1,1,1-trifluoroacetone instead of ethyl 3-bromo-2-oxopropanoate in step 5.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:10](=[O:13])[CH:11]=[CH2:12])=[N:7][CH:8]=1.C(O)C.O1CCCC1.[Cl:29][C:30]1[S:34][C:33]([CH:35]=[O:36])=[N:32][CH:31]=1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Cl:29][C:30]1[S:34][C:33]([C:35](=[O:36])[CH2:12][CH2:11][C:10](=[O:13])[CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][N:7]=2)[CH2:14][CH:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[N:32][CH:31]=1
Reactant: O=Cc1ncc(Cl)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)cn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(Cl)s2)nc1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 4-[5-(methylsulfanyl)pyridin-2-yl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (85.0 mg) in a mixed solvent of ethanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added 5-chloro-1,3-thiazole-2-carbaldehyde (86.0 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (7.9 mg) and triethylamine (16.3 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (98.4 mg, yield 77%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8]>CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Temperature: 25 °C
Yield: 108 %

Procedure:
To an ice cooled solution of methyl 5-chloro-2-(2-phenylpyrrolidin-1-yl)nicotinate (D72) (165 mg, 0.520 mmol) in methanol (10 ml), 10N NaOH (10 ml) was added. The mixture was heated under reflux overnight. After cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water (10 ml), acidified with 2.5N HCl (pH 1-2), and the resulting mixture was extracted with ethyl acetate (2×10 ml). The organic solution was washed with brine (20 ml), dried over Na2SO4 and evaporated in vacuo to afford the title compound (D98) (170 mg) as a red solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[NH:10][C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:10]([CH3:19])[C:9](=[O:11])[CH2:8][O:7][C:6]=2[N:12]=1
Reactant: O=C1COc2nc(Br)c(-c3ccccc3)cc2N1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (1.00 g, 3.28 mmol) in anhydrous N,N-dimethylformamide (5 mL), potassium carbonate (1.359 g, 9.83 mmol) and iodomethane (0.246 mL, 3.93 mmol) to give a brown suspension. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution (30 mL) and extracted into dichloromethane (3×15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give a brown oil. The residue was purified via Biotage chromatography (silica 50 g column, cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give a pale yellow solid (780 mg, 74.6% yield). 1H NMR (500 MHz, CDCl3): 7.51-7.44 (5H, m), 7.20 (1H, s), 4.91 (2H, s), 3.36 (3H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)#[N:16]>C(#N)C.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(COc2ccc(I)cc2)cc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4-iodo phenol (620 mg, 3.18 mmol) in acetonitrile (6 ml) was added K2CO3 (1.31 g, 9.54 mmol), followed by 4-cyanobenzyl bromide (700 mg, 3.18 mmol) at 20-35° C. and the reaction mixture was stirred at 80° C. for 6 h. The progress of the reaction was monitored by TLC. After 6 h of stirring, the mixture was cooled to 20-35° C., diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 10% ethyl acetate/hexane as an eluent to get the desired compound as a to pale yellow solid (800 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=8.3 Hz, 2H), 7.64-7.59 (m, 4H), 6.90-6.85 (m, 2H), 5.21 (s, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[Br:4][C:5]1[CH:6]=[C:7]([Cl:12])[C:8](Cl)=[N:9][CH:10]=1.O>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([Cl:12])[C:8]([NH:2][NH2:3])=[N:9][CH:10]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(Br)cc1Cl
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (50 ml) was stirred at 100° C., a solution of 5-bromo-2,3-dichloropyridine (15.0 g) in ethanol (25 ml) was added therein dropwise over an hour and the mixture was stirred at the same temperature. After completion of the reaction, the reaction solution was cooled to room temperature, water (150 ml) was added and stirred at the room temperature. The precipitated solid was collected by filtration to give (5-bromo-3-chloropyridin-2-yl)hydrazine (14.78 g) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:35])([CH3:34])[C@@H:14]([O:26]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][O:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:34])([CH3:35])[C@@H:14]([OH:26])[C:15]([O:17][CH2:18][O:19][C:20]([O:22][CH:23]([CH3:24])[CH3:25])=[O:21])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)OC(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCOC(=O)OC(C)C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Following the general procedure of hydrogenolysis of benzyl ethers of Description 18, a mixture of (methylethoxycarbonyloxy)methyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate (27c) (16 mg, 0.03 mmol) and 20 mg of 10 wt.-% of palladium on activated carbon in 2 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 11 mg (83% yield) of the title compound (27) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=1.01 (s, 3H), 1.13 (s, 3H), 1.33-1.35 (m, 6H), 2.00 (s, 3H), 2.07-2.11 (m, 2H), 3.13-3.26 (m, 2H), 3.35-3.45 (m, 2H), 3.97 (d, J=9.2 Hz, 1H), 4.12 (s, 1H), 4.16 (d, J=9.6 Hz, 1H), 4.94 (sept., J=6.4 Hz, 1H), 5.79 (d, J=5.6 Hz, 1H), 5.81-5.89 (br. m, 1H), 5.91 (d, J=5.6 Hz, 1H), ppm. MS (ESI) m/z: 428.04 (M+H)+, 450.02 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][CH:4]=1.[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CC(N(C)C)=O>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)[C@@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 90 °C
Yield: 46 %

Procedure:
4-Trifluoromethyliodobenzene (0.27 g, 1.0 mmol), D-valine (0.12 g, 1.0 mmol), potassium carbonate (0.21 g, 1.5 mmol), copper(I) iodide (19 mg, 0.10 mmol) and dimethylacetamide (1 mL) were charged in a threaded test tube, and the mixture was stirred with heating at 90° C. for 2 days. After work-up according to a conventional method, the object product was eluted by silica gel column chromatography (20% to 40% mixed solvent of ethyl acetate/hexane) to give the title compound (0.12 g, 0.46 mmol, 46%).
Reaction SMILES: Cl.[CH2:2]([NH2:5])[C:3]#[CH:4].N1C=CC=CC=1.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]>O1CCCC1>[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:5][CH2:2][C:3]#[CH:4])=[O:20])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C#CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
To a stirred solution of propargylamine hydrochloride (5.0 g, 54.6 mmol) and pyridine (7.8 g, 99.1 mmol) in tetrahydrofuran (30 mL) was added 4-nitro-benzoylchloride (9.2 g, 49.6 mmol) in tetrahydrofuran (20 mL) and the mixture was heated at reflux for 16 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to afford 4-nitro-N-prop-2-ynyl-benzamide (7.74 g, 77%) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23](Br)=[CH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[NH2:16][C:17]1[O:18][CH2:19][C@:20]2([N:37]=1)[C:33]1[CH:32]=[C:31]([OH:34])[C:30]([F:35])=[CH:29][C:28]=1[O:27][C:26]1[C:21]2=[CH:22][C:23]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1cc(F)c(O)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@]2(CO1)c1cc(C3=CCOCC3)ccc1Oc1cc(F)c(O)cc12
Temperature: 110 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (276 mg, 1.315 mmol), (S)-2-amino-7′-bromo-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (300 mg, 0.822 mmol), potassium phosphate (523 mg, 2.465 mmol) and Cl2Pdbis(di-tert-butyl(phenyl)phosphine) (15.28 mg, 0.025 mmol) in 3 ml of dioxane/water=2:1 was heated at 110° C. microwave for 30 min. The reaction mixture was purified by silica gel chromatography (DCM to DCM/MeOH=100:1 to 100:6) to give (R)-2-amino-7′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-])=O)[CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-])=O)[CH:24]=2)=[CH:4][CH:3]=1.C1COCC1>CN(C=O)C.[Pt]=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]([C:23]3[CH:24]=[C:25]([NH2:30])[C:26]([NH2:27])=[CH:28][CH:29]=3)[CH2:10][CH2:11][CH:12]2[C:13]2[CH:14]=[C:15]([NH2:20])[C:16]([NH2:17])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CCC(c3ccc(N)c([N+](=O)[O-])c3)N2c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1ccc(C2CCC(c3ccc(N)c(N)c3)N2c2ccc(F)cc2)cc1N
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4,4′-(1-(4-Fluorophenyl)pyrrolidine-2,5-diyl)bis(2-nitroaniline) (0.218 g, 0.50 mmol) was dissolved in DMF (5 mL) then platinum oxide (0.226 g, 0.99 mmol) was added as a THF slurry. The flask was evacuated and purged with nitrogen twice, then evacuated and opened to hydrogen balloon. The mixture was stirred at room temperature for 20 hours. The solution was taken on to the next step without purification.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][NH:13][CH2:14][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH3:27])[N:17]=2)[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCN(CCNC(=O)c2nn(CCC)c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN1CCN(CCNCc2nn(CCC)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
To a solution of N-[2-(4-n-butyl-1-piperazinyl)-ethyl]-1-n-propylindazole-3-carboxamide (0.36 g) obtained in Example 3 in THF (5 ml) was added lithium aluminum hydride (0.11 g) at room temperature, and the mixture was heated under reflux for 3 hours. The reaction solution was ice-cooled, and were successively added water (0.1 ml), a 15% aqueous sodium hydroxide (0.1 ml), water (0.3 ml) and THF (10 ml). After the reaction solution was stirred at room temperature for 30 minutes, the insolubles were filtered off with Celite. The filtrate was distilled off under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (chloroform:methanol:aqueous ammonia=8:2:0.2) to give the title compound (0.14 g) as a pale yellow oily substance. Yield=40%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2.Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:27][CH:26]=2)[CH:22]=[N:23]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]ncc4c3)c2cc1OC
Yield: 73.6 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.132 g of 5-aminoindazole, 0.020 g of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 2 hours. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrochloric acid to adjust pH to 7. The product was collected, washed with water, and dried to give 0.252 g of 4-(1H-indazol-5-ylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 290-295° C.; mass spectrum (EI, m/e): M 345.1217.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1.[K].[S-:19][C:20]#[N:21].[S-]C#N.[K+]>C(O)(=O)C>[S:19]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[N:3]=1)[C:20]#[N:21]
Reactant: FC(F)C(F)(F)c1nc(Cl)c2ccccc2n1
Reactant: N#C[S-]
Agent: [K+]
Agent: [K]
Solvent: CC(=O)O
Product: N#CSc1nc(C(F)(F)C(F)F)nc2ccccc12
Reaction time: 2 h

Procedure:
7.9 g of 4-chloro-2-(1,1,2,2-tetrafluoroethyl)-quinazoline are dissolved in 10 ml of glacial acetic acid and subsequently 4.9 g of potassium-thiocyanate are added to this solution. Whilst stirring at room temperature the potassium thiocyanate dissolves in approximately 1 hour. The solution is stirred for another 2 hours, a precipitation being obtained. This precipitation is drawn off, washed with water and dried in vacuo. After recrystallization from isoporpanol the resulting 4-thiocyano-2-(1,1,2,2-tetrafluoro-ethyl)-quinazoline has a melting point of 112°-114.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]=3[CH:37]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:38]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][C:20]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:19]=3[CH:37]=2)=[O:38])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CCCCCCC1(CCCCCC)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4,4-di-n-hexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH2:1]([CH:4]1O[CH:5]1[CH2:6][CH2:7][CH3:8])[CH2:2]C.B(F)(F)F.C[CH2:15][O:16]CC>C1C=CC=CC=1>[CH2:6]([CH:5]([CH2:4][CH2:1][CH3:2])[CH:15]=[O:16])[CH2:7][CH3:8]
Reactant: CCOCC
Reactant: CCCC1OC1CCC
Agent: FB(F)F
Solvent: c1ccccc1
Product: CCCC(C=O)CCC
Reaction time: 0.02 h
Yield: 75 %

Procedure:
To a vigorously stirred solution of 2 propyl 1,2 epoxypentane (1 equivalent), prepared as described in Example 1, in benzene cooled to 0° was added a solution of boron trifluoride etherate (0.5 equivalents) in benzene. The reaction mixture was stirred for 1 min and was quenched by the addition of water. Following separation of the phases, the organic phase was washed with saturated aqueous sodium bicarbonate and water, dried with magnesium sulfate, filtered and concentrated to give a colorless oil. The oil was distilled to give the desired product as a colorless oil; 75% yield; boiling point (b.p) 60-63° /0.1 mm.
Reaction SMILES: N[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][C:3]=1[CH3:21].[C:22](=[NH:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC([O-])(C)C.[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:22](=[N:35][C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([CH3:21])[CH:2]=1)[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])[CH:8]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1N
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1cc(N=C(c2ccccc2)c2ccccc2)cc(Oc2cc(NC(=O)C3CC3)ncn2)c1

Procedure:
Mix the cyclopropanecarboxamide derivative obtained in Step 2 (400 mg, 1.15 mmol), benzophenone imine (624 mg, 3.45 mmol), t-BuOK (257 mg, 2.3 mmol) and 1,4-dioxane in a 250 mL flask, add Xantphos (133 mg, 0.23 mmol), Pd(OAc)2 (26 mg, 0.115 mmol). Stir the reaction under N2 at 120° C. for 15 hrs.