Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17].C(=O)(O)[O-].[Na+].COC(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc(CCl)cc1OC1CCCC1
Temperature: 22.5 °C

Procedure:
A 12 liter round bottom flask equipped with an overhead stirrer, internal thermometer, and a reflux condensor equipped with a nitrogen inlet was flushed with nitrogen. The flask was charged with 3-cyclopentyloxy-4-methoxybenzyl alcohol (495 g, 2.2 mol, 1 equivalent) in a solution of toluene. To the vigorously stirred reaction at 22° C. was added concentrated hydrochloric acid (600 g, 2.75 equivalents). The reaction was maintained at 20 to 25° C. for 30 minutes. The top organic layer was isolated and the bottom acidic layer was discarded. To the top organic layer was charged a solution of 10% sodium bicarbonate (550 g, 0.65 mol, 0.36 equivalents) and t-butyl methyl ether (814 g). The contents of the flask were vigorously stirred, and allowed to settle. The product, 4-chloromethyl-2-cyclopentyloxy-1-methoxybenzene, was isolated as a solution in toluene and t-butyl methyl ether (96.8% solution yield). This was used directly in the next step.
Reaction SMILES: C(NC1C=C([N+]([O-])=O)C=C(NC(=O)CC)C=1)(=[O:4])CC.[C:20]([C:23]1[C:28](=[O:29])[O:27][C:26](=[O:30])[C:25](=[C:31](NC2C=C(NC(=O)CC)C=C(NC(=O)CC)C=2)[CH3:32])[C:24]=1[OH:50])(=[O:22])[CH3:21]>>[C:31]([C:25]1[C:26](=[O:30])[O:27][C:28]([OH:29])=[C:23]([C:20](=[O:22])[CH3:21])[C:24]=1[OH:50])(=[O:4])[CH3:32]
Reactant: CCC(=O)Nc1cc(NC(=O)CC)cc([N+](=O)[O-])c1
Reactant: CCC(=O)Nc1cc(NC(=O)CC)cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)c1
Product: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O

Procedure:
Following the procedures outlined in Example 2, this nitrobenzene was hydrogenated to the 3,5-bis-propionamidoaniline and the latter (2.15 g., 0.0084 mol) was reacted with 1.75 g. (0.0084 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one to furnish 5-acetyl-4-hydroxy-3-[1-(3,5-bis-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 239°-241° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl>COCCOC>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc([N+](=O)[O-])cc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc([N+](=O)[O-])cc1OCCN(C)C
Reaction time: 18 h
Yield: 86.2 %

Procedure:
A stirred solution of 2-methoxy-5-nitrophenol (10 g, 0.059 mole) in 1,2-dimethoxyethane (80 ml) was treated with saturated aqueous potassium carbonate solution (32 ml) followed by 2-dimethylaminoethyl chloride hydrochloride (8.2 g, 0.057 mole) and heated under reflux for 17 hours. A further quantity of 2-dimethylaminoethyl chloride hydrochloride (4.0 g, 0.029 mole) was added and reflux was continued for 18 hours. The mixture was then concentrated in vacuo and the residue treated with 10% Na2CO3 solution (100 ml) and extracted with ethyl acetate (2×100 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a yellow solid (11.8 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:32]N(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([OH:72])=[O:71])=[C:68]([O:75][CH3:76])[CH:67]=1>C(Cl)Cl>[CH3:32][O:71][C:70](=[O:72])[C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]2)=[O:30])=[CH:67][C:68]=1[O:75][CH3:76]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 118 mg, 0.31 mmol) was added followed by the addition of DIPEA (0.15 mL, 0.86 mmol) and 4-amino-2-methoxy-benzoic acid (Avocado, 62 mg, 0.34 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/methylene chloride) to give a white solid. 29 mg.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>OP(O)(O)=O>[CH2:14]([O:13][CH:12]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(OCC)OCC
Agent: O=P(O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)OCC
Yield: 92.5 %

Procedure:
160.2 g (1.0 mol) of diethyl malonate, 474.2 g (3.2 mol) of triethyl orthoformate and 0.5 g of catalyst from Example 5 were initially introduced and the mixture was heated to boiling. A mixture of 10 g of acetic anhydride, 1 g of H3PO4 and 30 g of triethyl orthoformate were continuously added dropwise over the course of 6 hours. The reaction and work up were carried out in accordance with Example 3 and gave 200 g of diethyl ethoxymethylenemalonate, which corresponds to a yield of 92.6% of the theoretical yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1>>[Br:7][C:8]1[CH:13]=[C:12]([N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])[CH:11]=[N:10][CH:9]=1
Reactant: O=C1CCCN1
Reactant: Brc1cncc(Br)c1
Product: O=C1CCCN1c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate B-8, pyrrolidin-2-one has been coupled to 3,5-dibromopyridine to yield the title compound as a light yellow solid. MS: 241.0, 243.0 (M+H+).
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([O:40][CH3:41])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[C:35]([O:40][CH3:41])[CH:36]=[CH:37][CH:38]=5)[CH:33]=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 1.5 h

Procedure:
To 1.5 mL of methanol solution containing 0.182 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.13 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-methoxyquinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: COC1C2N[C:10](=[O:21])C3C(=O)C4N=CC=CC=4C=3C=2C=CC=1.CO[C:24]1[C:29]2[NH:30][C:31](=O)[C:32]3[C:33](=[O:41])[C:34]4[CH:35]=[CH:36][CH:37]=[N:38][C:39]=4[C:40]=3[C:28]=2[CH:27]=[CH:26][CH:25]=1.CN(C=O)C.P(Cl)(Cl)([Cl:50])=O>>[Cl:50][C:31]1[C:32]2[C:33](=[O:41])[C:34]3[CH:35]=[CH:36][CH:37]=[N:38][C:39]=3[C:40]=2[C:28]2[CH:27]=[CH:26][C:25]([O:21][CH3:10])=[CH:24][C:29]=2[N:30]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc2c3c(c(=O)[nH]c12)C(=O)c1cccnc1-3
Reactant: COc1cccc2c3c(c(=O)[nH]c12)C(=O)c1ncccc1-3
Solvent: CN(C)C=O
Product: COc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cccnc1-3

Procedure:
The mixture of 4-methoxy-5H-5,8-diaza-benzo[c]fluorene-6,7-dione and 4-methoxy-5H-5,11-diaza-benzo[c]fluorene-6,7-dione (54 mg) obtained above and DMF (0.1 ml) were suspended in phosphorus oxychloride (2 ml) and refluxed for three hours. Excess phosphorus oxychloride was evaporated under reduced pressure. The residue was treated with water and saturated sodium hydrogen carbonate to adjust the pH about 7. Orange ppt was collected with suction and washed water. The ppt was purified by silica gel column chromatography developed by dichloromethane-methanol (200:1) and by dichloromethane-methanol (200:2). This chromatography gave two yellow bands. The first band was collected and evaporated to give the less polar isomer (11.3 mg), 6-chloro-3-methoxy-5,11-diaza-benzo[c]fluoren-7-one (Example 14c-1) as a yellow powder. The second band was collected and evaporated to give the more polar isomer (20.3 mg), 6-chloro-3-methoxy-5,8-diaza-benzo[c]fluoren-7-one (Example 14c-2) as a yellow powder.
Reaction SMILES: CO[C:3]1[CH:14]=[C:13]2[C:6]([NH:7][CH:8]=[C:9]2[CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[CH3:15]OC1C=C2C(=CC=1)C(CCN)=CN2.C(O)(C(F)(F)F)=O>C1COCC1>[CH2:15]1[C:8]2[NH:7][C:6]3[C:13](=[CH:14][CH:3]=[CH:4][CH:5]=3)[C:9]=2[CH2:10][CH2:11][NH:12]1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)CNCC3
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methoxy tryptamine 1a or 6-methoxy tryptamine 1b (0.524 mmol) and appropriate aryl or heteroaryl aldehyde 2 (0.63 mmol) were dissolved in THF (20 mL). The reaction mixture was cooled to 0° C. CF3COOH (0.2 ml) was then added at 0° C., and the reaction mixture was then allowed to stir at 0° C. for 1 hr. The ice bath was then removed and the reaction allowed to stir for a further 1 hr from 0° C. to r.t. The reaction mixture was quenched with aqueous saturated NaHCO3 (5 ml) and the organic phase separated. The mixture was extracted with EtOAc (2×10 ml). The combined organic phase was dried (anhydrous NaSO4), filtered and evaporated in vacuo to give the crude product tetrahydro β-carboline 3. The crude product was directly used for second step with out further purification.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.CN1CCOCC1.[Cl:20]C(OCC(C)C)=O.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[ClH:20].[NH2:8][CH2:9][C:10]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: C1CCNC1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cl
Product: NCC(=O)N1CCCC1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
tert-Butoxycarbonylaminoacetic acid (876 mg, 5.00 mmol) and N-methylmorpholine (506 mg, 5.00 mmol) were dissolved in tetrahydrofuran (20 ml). After isobutyl chloroformate (683 mg, 5.00 mmol) was added dropwise at below −15° C. and the reaction mixture was stirred for 30 minutes, pyrrolidine (782 mg, 11.0 mmol) was added at below −15° C. and the reaction mixture was further stirred at 0° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and 1N aqueous solution of sodium hydroxide. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, and was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained residue was dissolved in a solvent mixture of ethyl acetate (10 ml)-tetrahydrofuran (5 ml). 4N hydrochloric acid Ethyl acetate solution (5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. After the solvent was distilled off, ethyl acetate was added to the crude product to precipitate crystals; and the crystals were filtered off and dried under aeration to yield 2-amino-1-(pyrrolidin-1-yl)ethanone hydrochloride (573 mg, 4.16 mmol, 84%) as white crystals.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.C(OCC)C.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.[Cu](I)I>[OH:17][C:18]1[CH:27]=[C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:14]=[C:13]3[C:8]([C:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][S:12]3)=[CH:7][CH:6]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: C#CC(O)c1ccc2c(c1)SCCC2(C)C
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)SCCC3(C)C)cc1O
Reaction time: 4 h

Procedure:
2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-7-thiochromanmethanol, 3 g (10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 600 mg (0.86 mmol) of bis(triphenylphosphine)palladium(II) chloride and 240 mg (1.3 mmol) of copper iodide were successively added. Stirring was carried out at room temperature for four hours and the reaction mixture was evaporated to dryness and the residue obtained taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 3.2 g (80%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-7-yl)-1-propynyl]benzoate, with a melting point of 101°-102° C., were recovered.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]1C2NC3C(=CC=C(C(O)=O)C=3)C=2CCC1.[CH2:21]1[C:33]2[NH:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:34]([OH:36])=[O:35])[C:26]=3[C:25]=2[CH2:24][CH2:23][CH2:22]1>CO>[CH2:21]1[C:33]2[NH:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:34]([O:36][CH3:5])=[O:35])[C:26]=3[C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)c1ccc2c3c([nH]c2c1)CCCC3
Reactant: O=C(O)c1cccc2[nH]c3c(c12)CCCC3
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2[nH]c3c(c12)CCCC3

Procedure:
By adding thionyl chloride to a methanol solution of a mixture of 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid and 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid at −10° C., followed by the reaction under heating and subsequent separation and purification by a column chromatography, methyl 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylate [Reference Example 17a: ESI: 2230 (M+H)+] and methyl 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylate [Reference Example 17b: ESI: 230 (M+H)+] were obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:42]=[CH:41][C:10]([C:11]([O:13][C@@H:14]3[CH2:22][C@@H:17]4[O:18][C:19](=[O:21])[CH2:20][C@@H:16]4[C@H:15]3/[CH:23]=[CH:24]/[C@@H:25]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>[Pd].CC#N>[C:1]1([C:7]2[CH:42]=[CH:41][C:10]([C:11]([O:13][C@@H:14]3[CH2:22][C@@H:17]4[O:18][C:19](=[O:21])[CH2:20][C@@H:16]4[C@H:15]3[CH2:23][CH2:24][C@@H:25]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of a compound [7a] (80.0 g), palladium on carbon catalyst (16 g) and ethyl acetate (1.0 L) was stirred under hydrogen atmosphere at 150 psi for 3 hours at room temperature. The reaction mixture was then filtered and evaporated under reduced pressure. The oily residue was crystallized from a mixture of hexane and ethyl acetate 4:1 v/v to give 71.4 g (89% yield) of compound [9a], mp 103-105° C., [α]D20 −107° (c 1.0, MeCN). 1H NMR (CDCl3) δ: 8.03 (d, J=8 Hz, 2H); 7.60-7.67 (m, 4H); 7.36-7.48 (m, 3H); 7.14-7.24 (m, 5H); 5.20-5.30 (m, 1H); 5.00-5.15 (m, 1H); 4.50-4.70 (m, 1H), 3.89-3.95 (m, 1H); 3.66-3.72 (m, 1H); 3.45-3.50 (m, 1H). 13C NMR (CDCl3) δ: 20.1; 25.4; 28.7; 31.3; 31.9; 36.5; 43.5; 52.8; 63.0; 76.0; 80.1; 84.3; 97.8; 125.7; 127.1; 127.2; 128.1; 128.3; 128.4; 128.9; 130.1; 140.0; 142.4; 146.0; 165.8; 176.7. IR (KBr): 2990; 1771; 1707; 1608; 1277; 1181; 1110; 1026; 751; 698 cm−1.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:27](=[O:28])[C:26]([C:29]([NH2:31])=[O:30])=[C:25]([OH:32])[C@:24]2([OH:33])[C@H:5]1[CH2:6][C@H:7]1[C:21]([C:22]2=[O:23])=[C:20]([OH:34])[C:10]2[C:11]([OH:19])=[C:12]([NH2:18])[CH:13]=[C:14]([N:15]([CH3:17])[CH3:16])[C:9]=2[CH2:8]1)[CH3:3].[C:35]([N:39]([C:51]([O:53][CH2:54][CH:55]([CH3:57])[CH3:56])=[O:52])[CH2:40][C:41](OC(OCC(C)C)=O)=[O:42])([CH3:38])([CH3:37])[CH3:36]>>[NH2:31][C:29]([C:26]1[C:25](=[O:32])[C@:24]2([OH:33])[C@@H:5]([CH2:6][C@H:7]3[C:21](=[C:22]2[OH:23])[C:20](=[O:34])[C:10]2[C:11]([OH:19])=[C:12]([NH:18][C:41](=[O:42])[CH2:40][N:39]([C:35]([CH3:36])([CH3:38])[CH3:37])[C:51](=[O:52])[O:53][CH2:54][CH:55]([CH3:56])[CH3:57])[CH:13]=[C:14]([N:15]([CH3:16])[CH3:17])[C:9]=2[CH2:8]3)[C@H:4]([N:2]([CH3:1])[CH3:3])[C:27]=1[OH:28])=[O:30]
Reactant: CN(C)c1cc(N)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Reactant: CC(C)COC(=O)OC(=O)CN(C(=O)OCC(C)C)C(C)(C)C
Product: CC(C)COC(=O)N(CC(=O)Nc1cc(N(C)C)c2c(c1O)C(=O)C1=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C[C@@H]1C2)C(C)(C)C

Procedure:
The title compound is prepared by the procedure of Example 42, using 1 equivalent of 9-amino-minocycline and 2 equivalents of isobutoxycarbonyl N-(tert-butyl)-N-(isobutoxycarbonyl)glycinate, Reference Example 119 to give the product of the example.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4][CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12]>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:12]
Reactant: CCC(N)CC
Reactant: COc1ccc(C(=O)O)cc1Cl
Product: CCC(CC)NC(=O)c1ccc(OC)c(Cl)c1
Yield: 40 %

Procedure:
Prepared in a similar manner to example 4 using 3-pentylamine and 3-chloro-4-methoxy benzoic acid. Yield 40%. MS (M+H, 256.20).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CO.CC(O)=O.[Br:19]Br>>[Br:19][C:4]1[CH:3]=[C:2]([CH3:1])[CH:11]=[C:10]2[C:5]=1[C:6](=[O:12])[NH:7][CH:8]=[N:9]2
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(Br)c2c(=O)[nH]cnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.9 %

Procedure:
To a solution of 7-methylquinazolin-4(3H)-one (900 mg, 5.63 mmol) in MeOH (180 mg, 5.63 mmol) and AcOH (5.07 g, 84.45 mmol) was added bromine (300 μL, 5.63 mmol) and the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with an aq. solution of sodium thiosulphate. The precipitate obtained was filtered and dried to afford 900 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 12.24 (br s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.66 (s, 1H), 2.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][O:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: ClCCOc1cccnc1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCOc1cccnc1
Temperature: 90 °C
Yield: 21.5 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), 3-(2-chloroethoxy)pyridine hydrochloride (234 mg, 1.2 mmol) and potassium carbonate (456 mg, 3.3 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(3-pyridyloxy)ethoxy)quinazoline (95 mg, 20%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:6]=1[CH:7](O)[CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH:7]([C:6]1[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:3][C:2]=1[CH3:1])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(O)c1cc(-c2ccccc2)oc1C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCC(Cl)c1cc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-(2-methyl-5-phenylfuran-3-yl)pentan-1-ol (1.6 g) in toluene (20 mL) was added thionyl chloride (1.0 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.7 g, 100%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:18]1[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=1>>[CH3:1][CH:2]1[O:16][C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:18]3[CH:19]=[C:20]([C:23]#[N:24])[S:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCC2)O1
Reactant: N#Cc1cc(Br)cs1
Product: CC1Nc2ccc(-c3csc(C#N)c3)cc2C2(CCCC2)O1

Procedure:
Prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclopentane] and 4-bromo-2-thiophenecarbonitrile. An off-white solid: mp 103-104° C.
Reaction SMILES: [Li]CCCC.[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][CH:13]=[CH:14][CH:15]=1.[Sn:16](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:25]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[C:7]1([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:8][CH:9]=[CH:10][O:6]1)[CH2:26][CH2:27][CH3:28]
Reactant: c1coc(-c2ccco2)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)C1(c2ccco2)CC=CO1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of n-BuLi (7.7 mL, of 2.5M in hexanes, 19.2 mmol, 1.3 equivalents) was added dropwise to a solution of bifuran (2 g, 14.9 mmol) in dry THF (100 mL) at −78° C. under N2. The mixture was allowed to come to room temperature and stirred for 1 h. To the white suspension was added dropwise Bu3SnCl (4 mL, 14.9 mmol) at 0° C. and the reaction was allowed to reach room temperature and stirred for 2 h. The mixture was extracted with hexane, dried (MgSO4) and evaporated. Seperation by chromatography using bacified silica (Et3N) and hexane gave 1 (3.8 g, 60% yield) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 0.85-0.91 (t, J=7.3 Hz, 9H), 1.03-1.13 (m, 6H), 1.26-1.39 (m, 6H), 1.48-1.63 (m, 6H), 6.40-6.42 (m, 1H), 6.50 (d, J=3.3 Hz, 1H), 6.57 (dd, J=3.3, 6.0 Hz, 2H), 7.34 (dd, J=0.7, 1.8 Hz, 1H) ppm. 13C NMR (300 MHz, CDCl3): δ 10.2, 13.7, 27.2, 28.9, 104.6, 105.0, 111.3, 123.0, 141.4, 147.5, 151.0, 160.9 ppm