Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O.[Br:18]Br>C(O)(=O)C.O.[N+]([O-])([O-])=O.[Ag+]>[Br:18][C:13]1[CH:12]=[C:8]([CH:7]=[CH:6][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: BrBr
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)O)cc1Br
Yield: 36.5 %

Procedure:
4-tert-butyl benzoic acid (500 mg, 2.8 mmol) was stirred rapidly in acetic acid (11 mL), nitric acid (1.7 mL) and bromine (114 μL, 5.9 mmol). To this was added a solution of silver nitrate (1.01 g, 5.9 mmol) in water (5 mL). A thick yellow precipitate resulted and further acetic acid was added (2 mL) before heating at reflux for 1 h. The hot solution was filtered and water added to the filtrate until a white solid precipitated. The solid was filtered, air dried and recrystallised from acetic acid to give 3-bromo-4-tert-butyl-benzoic acid as a white solid (263 mg, 36%). 1H NMR (CDCl3, 300 MHz) δ 1.85 (s, 9H, (CH3)3), 7.86 (d, 1H, J=8.5 Hz, ArH), 8.26 (dd, 1H, J=2.0, 8.5 Hz, ArH), 8.62 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](=[NH:14])OCC.C(O)C.[NH2:18][NH:19][C:20]([NH2:22])=[S:21]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:18][NH:19][C:20]([NH2:22])=[S:21])=[NH:14]
Reactant: NNC(N)=S
Reactant: CCOC(=N)c1ncc([N+](=O)[O-])n1C
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c([N+](=O)[O-])cnc1C(=N)NNC(N)=S

Procedure:
To a stirred solution of ethyl 1-methyl-5-nitro-2-imidazolecarboximidate (0.198 g., 0.001 mole) in 10 ml. of absolute ethanol is added thiosemicarbazide (0.091 g., 0.001 mole) and 1 ml. of glacial acetic acid. The mixture is heated at reflux for 11/4 hours and is cooled in an ice bath. The orange-red solid is filtered washed and dried affording 0.173 g. of the title compound, melting point 210°-214°, dec.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C>[OH-].[Na+]>[O:16]=[C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=[C:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c[nH]c2ccccc2c1=O
Reaction time: 2 h
Yield: 80.4 %

Procedure:
4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) was suspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 h under reflux. After cooling, the mixture was filtered, and the filtrate was acidified to pH 4 with 2N HCl. The resulting precipitate was collected via filtration, washed with water and dried under vacuum to give 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale white solid (10.5 g, 92%). 1H NMR (d-DMSO) δ15.34 (s, 1 H), 13.42 (s, 1 H), 8.89 (s, 1H), 8.28 (d,J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d,J=8.4 Hz, 1H), 7.60 (m, 1H).
Reaction SMILES: [C:1](O)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].ClCC(OC(=O)CCl)=O.[O:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>C1(C)C=CC=CC=1>[C:1]([C:20]1[O:19][CH:23]=[CH:22][CH:21]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)O
Reactant: c1ccoc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Product: CCCCCCC(=O)c1ccco1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 91 %

Procedure:
In 50 ml of toluene were dissolved 6.51 g (0.05 mole) of heptanoic acid and 10.26 g (0.06 mole) of monochloroacetic anhydride. To the resulting solution were added 4.43 g (0.065 mole) of furan and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 50° C. for 5.5 hours. After completion of the reaction, the reaction solution was cooled and washed with 5% aqueous sodium carbonate solution and water in this order. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 8.2 g of 2-heptanoylfuran.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1CNC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), alpha-bromo-o-xylene (74.02 mg, 0.40 mmol) and K2CO3 (166.0 mg, 1.20 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cool to r.t., the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give an oil which was purified by preparative TLC, eluted with 50% nHex/EtOAc to give 2-(2-methyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (58.0 mg, 42.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C=O.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:21])[CH:13]([P:15]([O:19][CH3:20])([O:17][CH3:18])=[O:16])[O:14][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COP(=O)(OC)C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(O[Si](C)(C)C(C)(C)C)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a mixture of 3.48 g of product from Example 97 and 12 ml of dimethylformamide is added 1.86 g of t-butyldimethylsilyl chloride and 1.86 g of imidazole. After stirring the reaction at room temperature for 2 hours, the mixture is diluted with ethyl acetate/diethyl ether, washed 5 times with water, once with saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer is dried, filtered and concentrated in vacuo to give 3.90 g of the desired silylated product.
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>C1COCC1>[NH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:6]([NH2:5])=[O:7])=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: NCc1ccc(N)cc1
Solvent: C1CCOC1
Product: NC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trimethylsilylisocyanate (3.2 ml; 85%) was added to a solution of 4-amino-benzylamine (1.55 ml) in dry THF (40 ml). A white solid precipitated. The reaction mixture was stirred at r.t. overnight then the precipitate was filtered and washed with ethyl acetate giving the title compound (1.2 g) as a white solid.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([N+:17]([O-])=O)=[C:8]([CH:20]([CH3:22])[CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.O.[Sn](Cl)Cl>C(O)C>[N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)[C:9]([NH2:17])=[C:8]([CH:20]([CH3:22])[CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1nc(-n2ccnc2)nc(-n2ccnc2)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolve 2,4-bis(1H-imidazol-1-yl)-5-nitro-6-(2-propyl)pyrimidine (16 g, 53.5 mmol) in 300 mL of ethanol and add 35 g of tin (II) chloride dihydrate. Stir for 2 hours at ambient temperature. Remove the solvent under vacuum and slurry the residue in 2 L of CH2Cl2. Wash with 2×3 L 10% KOH. Dry the CH2Cl2 portion over MgSO4, treat with charcoal, filter, and concentrate the filtrate under vacuum. Crystallize the residue from ethyl acetate to provide 2,4-bis(1H-imidazol-1-yl)-6-(2-propyl)pyrimidin-5-amine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[N:13][C:14]([N:17]([C@H:19]2[CH2:24][CH2:23][C@H:22]([C:25]#[C:26][CH2:27][N:28]([CH3:30])[CH3:29])[CH2:21][CH2:20]2)[CH3:18])=[N:15][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:30][N:28]([CH3:29])[CH2:27][C:26]#[C:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([N:17]([CH3:18])[C:14]2[N:13]=[CH:12][C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:16][N:15]=2)[CH2:24][CH2:23]1
Reactant: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CN(C)CC#C[C@H]1CC[C@H](N(C)c2ncc(-c3ccncc3)cn2)CC1
Temperature: 85 °C
Reaction time: 17 h

Procedure:
In this reaction, the solvents were degased with argon for 10 minutes. A suspension of 7.3 mg PdCl2(dppf), of 29.4 mg (0.24 mmol) of 4-pyridylboronic acid an of 70 mg (0.2 mmol) of trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-amine in 3.5 ml dioxane were treated with 1 ml of an aqueous solution of 2M Na2CO3. After 17 h at 85° C., 7 mg of PdCl2(dppf) were added and the reaction was heated further at 85° C. for 24 h. The mixture was partitioned between aqueous saturated NaHCO3/Et2O (3×) and the combined organic phases were extracted with 0.1M HCl. The HCl-phase was adjusted to pH 14 (1 N NaOH) and extracted with Et2O (3×). The organic phase was washed with 10% NaCl and dried over Na2SO4 to yield after purifiction with flash-chromatography on silica gel (CH2Cl2/MeOH 99:1 to 9:1) 9 mg (13%) of trans-[4-(3-Dimethylamino-prop-1-ynyl)-cyclohexyl]-methyl-(5-pyridin-4-yl-pyrimidin-2-yl)-amine, MS: 350 (MH+).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].Br[C:9]1[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.Cl[Pd]Cl.O1CCCC1>[CH3:15][C:12]1[N:11]=[N:10][C:9]([CH:1]=[CH2:2])=[CH:14][CH:13]=1
Reactant: Cc1ccc(Br)nn1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C)nn1
Temperature: 77.5 °C

Procedure:
Potassium vinyltrifluoroborate (Aldrich, 1.71 g, 12.7 mmol), 3-bromo-6-methylpyridazine (Example 148A, 1.95 g, 11.3 mmol) and triphenylphosphine (0.18 g, 0.67 mmol) were added at room temperature to a solution of Cs2CO3 (10.1 g, 31.0 mmol) in water (9.5 mL). Tetrahydrofuran (85 mL) was added, and the reaction flask was evacuated and purged with nitrogen (3 cycles). PdCl2 (50 mg, 0.28 mmol) was added, and the reaction flask was again evacuated and purged with nitrogen (3 cycles), then heated under nitrogen at 75-80° C. for 22 hours. The mixture was cooled to room temperature and the aqueous layer was separated and extracted with ethyl ether (3×50 mL). The combined organic phase was concentrated to a volume of approximately 5 mL, and the residue was purified by flash chromatography (80 g silica, eluted with hexanes-ethyl acetate, 100:0-90:10): 1H NMR (300 MHz, methanol-d4) δ ppm 2.71 (s, 3H) 5.63 (d, J=11.2 Hz, 1H) 6.18 (d, J=18.3 Hz, 1H) 7.04 (dd, J=17.8, 11.0 Hz, 1H) 7.23-7.34 (m, J=8.8 Hz, 1H) 7.49 (d, J=8.8 Hz, 1H).
Reaction SMILES: [SH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+].Cl>CCOCC.N1C=CC=CC=1>[CH2:23]([O:22][C:20]([S:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:21])[CH3:24]
Reactant: O=C(O)C(S)c1ccc(-c2ccccc2Cl)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOC(=O)SC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A solution of α-mercapto-2'-chloro-4-biphenylylacetic acid 5.6 g. (0.02 moles) in 25 ml. of pyridine is cooled in an ice bath. To this is added dropwise 2.1 ml. (0.022 moles) of ethyl chloroformate. The mixture is basified with 10% sodium bicarbonate solution. The alkaline mixture is worked with ether, then acidified with 10% hydrochloric acid, washed with ether, dried and filtered. The solvent is removed and the residue is triturated with hexane to obtain α-ethoxycarbonylthio-2'-chloro-4-biphenylylacetic acid.
Reaction SMILES: [OH-].[Na+].Cl.[Cl:4][C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][CH2:10][CH:11]([NH:15][CH3:16])[CH2:12][C:13](=[O:14])[C:7]=2[CH:6]=1>O>[Cl:4][C:5]1[CH:18]=[CH:17][C:8]2[CH2:9][CH2:10][CH:11]([NH:15][CH3:16])[CH2:12][CH:13]([OH:14])[C:7]=2[CH:6]=1
Reactant: CNC1CCc2ccc(Cl)cc2C(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC1CCc2ccc(Cl)cc2C(O)C1
Temperature: 10 °C
Yield: 92.7 %

Procedure:
Sodium hydroxide solution was added to suspension of 4.6 g of the product of Step B in 100 ml of water cooled to 10° C and the mixture was extracted with methylene chloride. The extracts were dried and evaporated to dryness and the 4 g of oily residue were dissolved in 40 ml of ethanol and 4 ml of water. 2 g of sodium borohydride were added to the mixture at 20° C and the mixture was stirred for an hour. The mixture was evaporated to dryness and the residue was taken up in methylene chloride. The solution was washed with water, dried and evaporated to dryness. The residue was washed with isopropyl ether to obtain 3.7 g of 3-chloro-5ξ-hydroxy-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene melting at 90° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of (3S)-1-[(3-Bromophenyl)methyl]-3-methylpiperazine (250 mg, 0.5 mmol), TEA (0.5 ml, 3.5 mmol), and DMAP (12 mg, 0.1 mmol) in 1 mL of dry DMSO was added dropwise benzyl chloroformate (0.34 mL, 2.25 mmol) at 10° C. while stirring. The mixture was then heated and stirred at 50° C. for 1.5 h. After cooling to room temperature, 15 mL of ethyl acetate and 5 mL of saturated NaHCO3 were added. The organic layer was separated, concentrated under vacuum and purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (180 mg, 70%). LC/MS: m/z, 403 (M+H), 1.74 min.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.[Si](I)(C)(C)C>C(Cl)(Cl)Cl>[S:15]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[CH:13]=[CH:14]1
Reactant: CCOC(=O)N1CCc2ccsc2CC1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: c1cc2c(s1)CCNCC2
Temperature: 70 °C

Procedure:
The product of step d) (200 mg, 0.89 mmol) was dissolved in 15 mL CHCl3 and treated with TMSI (4.5 mmol, 600 uL). After heating to 70° C. overnight, the reaction was carefully quenched with MeOH (10 mL) and 1 M NaOH (20 mL). The subtitle compound was extracted into DCM (3×20 mL). The extracts were dried over MgSO4 and concentrated to give 178 mg of the subtitle compound. 1H NMR (300 MHz, DMSO) 7.20 (d, J=5 Hz, 1H), 6.85 (d, J=5 Hz, 1H), 3.42-3.61 (m, 4H), 2.71-3.03 (m, 4H). MS: ESI (positive): 154 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:21][O:22][CH2:23]OC>ClCCl>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: COCOC
Reactant: O=Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COCOc1ccc(C=O)cc1
Reaction time: 66 h

Procedure:
A suspension of 4-hydroxybenzaldehyde (55 g) and toluene-4-sulphonic acid (1.0 g) was stirred at reflux in a mixture of dichloromethane (500 ml) and dimethoxymethane (250 ml) under a Soxhlet extraction apparatus containing Type 3A molecular sieve (100 g). After 2 hours' reflux the molecular sieve was replaced with a fresh batch, and more toluene-4-sulphonic acid (1.0 g) was added to the reaction mixture. After 48 hour's reflux, the molecular sieve was changed again. After 66 hours' continuous reflux, the mixture was cooled and filtered to remove suspended solid. The filtrate was washed five times with 200 ml portions of N NaOH solution (i.e., until the NaOH solution was colourless after washing), and then it was washed with water and dried over anhydrous MgSO4. Removal of the solvent gave 4-(methoxymethoxy)benzaldehyde (47 g) as a light brown oil. This was used without further purification.
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[H][H]>[Ni]>[CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: c1cc2c3c(cccc3c1)CC2
Reactant: [H][H]
Agent: [Ni]
Product: C1CC2CCCC3CCC(C1)C23
Reaction time: 7 h
Yield: 100 %

Procedure:
A shaking autoclave having an internal volume of about 60 ml was charged with 5 grams of acenaphthene and 0.2 gram of a 50% Ni/kieselguhr catalyst and with hydrogen at an initial pressure of 200 kg/cm2 gauge. Reaction was effected at 200° C. for 7 hours. Perhydroacenaphthene was produced in a yield of 100%, and the combined selectivity of Nos. 1 and 3 trans-isomers was 96%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)[N:9]=[C:8]2[NH:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[N:32]=[CH:31]2)(=[O:3])[CH3:2]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Cl)c2cc1OC(C)=O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Solvent: CC(C)O
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OC(C)=O
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-7-methoxy-2-(3-nitrophenyl)quinazolin-6-yl acetate (1.60 g, 4.23 mmol) and tert-butyl 5-amino-1H-indazole-1-carboxylate (1.0 g, 4.28 mmol) were refluxed in anhydrous iso-propanol (60 mL) for 5 h. The mixture was allowed to cool to RT, upon which the solid was collected via filtration and was washed with Et2O to give tert-butyl 5-(6-acetoxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (2.2 g, 4.23 mmol, 100%). HPLC retention time=7.75 mins.
Reaction SMILES: CN1CCOCC1.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([N:22]3[CH2:29][CH2:28][CH2:27][C@@H:23]3[C:24]([OH:26])=O)=[O:21])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(OCC)=O.Cl.[Br:37][C:38]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:39]=1[CH2:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Br:37][C:38]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:39]=1[CH2:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:24]([C@H:23]1[CH2:27][CH2:28][CH2:29][N:22]1[C:20](=[O:21])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1)=[O:26]
Reactant: Nc1ccccc1OCc1cc(F)ccc1Br
Reactant: O=C(O)[C@H]1CCCN1C(=O)Cc1ccc(N2CCCC2)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1OCc1cc(F)ccc1Br)[C@H]1CCCN1C(=O)Cc1ccc(N2CCCC2)cc1
Reaction time: 2 h

Procedure:
Toluene (37.8 ml) and N-methylmorpholine (1.10 g, 10.8 mmol) were added to N-[(4-pyrrolidinophenyl)acetyl]-D-proline (2.90 g, 9.59 mmol). Ethyl chloroformate (1.14 g, 10.5 mmol) was added to the obtained mixture in an ice bath, and they were stirred for 2 hours. 2-(2-Bromo-5-fluorobenzyloxy)aniline hydrochloride (3.19 g, 9.59 mmol) and N-methylmorpholine (1.16 g, 11.5 mmol) were added thereto and the temperature of the obtained mixture was slowly elevated to room temperature for a period of 16 hours. Water (30 ml), citric acid (1.61 g) and toluene (10 ml) were added to the reaction mixture for the distribution. The organic layer was washed with water (10 ml), water (10 ml), 6.7% aqueous sodium hydrogencarbonate solution (10 ml), 6.7% aqueous sodium hydrogencarbonate solution (10 ml), water (10 ml) and water (10 ml). After drying over sodium sulfate, the solvent was evaporated under reduced pressure to obtain the title compound in the form of a light yellow solid (5.13 g, 93%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:16]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc2ccccc2c1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added naphthalen-2-ylboronic acid (1.292 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g) and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was washed with acetonitrile to give the title compound (0.876 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].N1C=CC=CC=1.[CH2:16]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl>C(Cl)Cl.O>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:39][CH:38]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Nc1cccc(CO)c1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2cccc(CO)c2)cc1
Reaction time: 6 h
Yield: 82.1 %

Procedure:
To a solution of 8.17 g of m-aminobenzyl alcohol and 16.14 g of pyridine in 200 ml of methylene chloride is added at 0° C. over 30 minutes a solution of 18 g of p-tetradecyloxybenzoyl chloride in 200 ml of methylene chloride. Stirring is continued for another 6 hours. An additional 400 ml of chloroform and water is added followed by warming to dissolve all the solids. The warm organic layer is separated and washed with dilute hydrochloric acid and saturated sodium bicarbonate. The warm organic layer is dried and filtered. The filtrate is diluted with an equal volume of hexane and cooled in a refrigerator overnight. The resulting solid is collected and air dried to give 18.4 g of the desired product as a white solid, m.p. 112°-115° C.