Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3](Br)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])C.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][CH:3]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:6])=[O:5])=[O:21]
Reactant: COC(=O)c1sccc1N
Reactant: CCC(Br)(C(=O)O)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1sccc1NC(C(=O)O)c1ccccc1

Procedure:
A solution of ethyl 2-bromo-2-phenylacetic acid (600 mg, 2.79 mmol) and methyl 3-aminothiophene-2-carboxylate (438 mg, 2.79 mmol) in acetonitrile (20 ml) was heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated to dryness and the resulting residue was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]3[N:15]=[C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([NH:23]C(=O)C(C)(C)C)=[N:21][CH:22]=4)[N:13]=[CH:12][C:7]=3[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO.O>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([NH:16][C:14]2[N:13]=[CH:12][C:7]3[CH2:8][C:9](=[O:11])[NH:10][C:4]4[CH:3]=[C:2]([Cl:1])[CH:31]=[CH:30][C:5]=4[C:6]=3[N:15]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cn1
Temperature: 100 °C
Reaction time: 22 h
Yield: 70.9 %

Procedure:
To a solution of N-{5-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]pyridin-2-yl}-2,2-dimethylpropanamide (0.220 g, 0.38 mmol) in THF (3 mL) and MeOH (4 mL) at rt was added 6M HCl in water (5 mL). The solution was allowed to stir at 100° C. for 22 h. The organic solvents were allowed to boil off and the aqueous mixture was allowed to cool to rt. Solid K2CO3 was added and the mixture was filtered. The resulting solid was collected and purified by column chromatography to give 2-[(6-aminopyridin-3-yl)amino]-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.095 g, 71%).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[CH2:11]([NH2:13])[CH3:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.O>[CH2:8]([O:7][C:5](=[O:6])[C:4]([NH:13][CH2:11][CH3:12])=[O:10])[CH3:9]
Reactant: CCN
Reactant: CCOC(=O)C(=O)OCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.3 %

Procedure:
To 135,8 ml (1000 mM) of diethyloxalate and 1 g of aliquat 336, in 1000 ml of dichloromethane, were added 64 ml (1000 mM) of ethylamine at 70% in water. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was removed under vacuum to give an oil, which was further purified by silica gel column chromatography, using dichloromethane/dimethylketone (95/5) as eluant, to give 59.9 g of ethyl(ethyl amino)(oxo)acetate as an oil.
Reaction SMILES: [Mo:1](=[O:4])(=[O:3])=[O:2].[P:5](=O)([OH:8])([OH:7])[OH:6]>O>[OH:7][PH:5]([OH:8])=[O:6].[OH:2][Mo:1]([OH:6])(=[O:4])=[O:3]
Reactant: O=[Mo](=O)=O
Reactant: O=P(O)(O)O
Solvent: O
Product: O=[Mo](=O)(O)O
Product: O=[PH](O)O
Reaction time: 3 h

Procedure:
A slurry was prepared of 86.4 (0.06 mole Mo) of molybdenum trioxide and 7.6 g. (0.067 mole P) of 85% phosphoric acid in 500 mls. of distilled water; boiled with stirring for three hours to form phosphomolybdic acid which was yellowish green in color. To this slurry was added 2.5 g. (0.0125 mole Cu) of copper acetate; no change in color, followed by the addition of 7.9 g. (0.025 mole Bi) of bismuth chloride dissolved in 4.0 ml. of concentrated hydrochloric acid. The mixture was boiled to dryness; dried overnight at 110° C. in air. The catalyst was ground and screened to 20/30 mesh fraction and calcined for three hours at 400° C. in 40 ml/min. air.
Reaction SMILES: [Cl-:1].[Ce+3].[Cl-].[Cl-].[I-].[Na+].Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1>O1CCCC1>[ClH:1].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][C:28]([CH2:8][C:9](=[O:10])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:31])[CH2:27][CH2:26]1
Reactant: [Cl-]
Reactant: O=C(CBr)c1ccccc1
Reactant: COc1ccccc1N1CCC(=O)CC1
Agent: [Ce+3]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1N1CCC(O)(CC(=O)c2ccccc2)CC1
Product: Cl
Yield: 34.5 %

Procedure:
Anhydrous cerium chloride (0.99 g, 4.0 mmol) and sodium iodide (1.8 g, 12.0 mmol) are added to 10 ml of anhydrous tetrahydrofuran as a solvent to form a suspension. 0.80 g (4.0 mmol) of bromoacetophenone and 0.82 g (4.0 mmol) of N-(2′-methoxyphenyl)-4-piperidone are dissolved into 10 ml of anhydrous tetrahydrofuran, and the solution is added dropwise to the above suspension. Operating according to the post-treatment procedure in General Method three obtains 0.5 g of a white crystal, with yield of 38.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH2:10][C:9](=O)[C:8]=2[CH:19]=1)([O-:3])=[O:2].C[Si]([C:24]#[N:25])(C)C.P(Cl)(Cl)(Cl)=O.Cl>[I-].[Zn+2].[I-].N1C=CC=CC=1.C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][S:14][CH2:13][CH2:12]3)[CH:10]=[C:9]([C:24]#[N:25])[C:8]=2[CH:19]=1)([O-:3])=[O:2]
Reactant: O=C1CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Reactant: C[Si](C)(C)C#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: N#CC1=CC2(CCSCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C

Procedure:
To a mixture of 3.08 g of 3,4-dihydro-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-one and 40 ml of dried benzene was added 1.8 ml of trimethylsilyl cyanide with stirring under ice-cooling. 1.22 g of zinc iodide was added therein and the resultant mixture was stirred at room temperature for 19 hours. 6 ml of pyridine and 3.1 ml of phosphorus oxychloride were added therein and the mixture was refluxed with heating for 5.5 hours. Ice water was added to the residue, and the residue was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.28 g of 6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydrothiopyran]-4-carbonitrile with a melting point of 175°-176° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1.C(N(CC)C(C)C)(C)C>C(COC)OC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[N:17][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)c1ccc(CBr)cn1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(Cc2cccc(F)c2)cn1
Yield: 264.2 %

Procedure:
A mixture of 3-fluorophenylboronic acid (0.319 g; 2.28 mmol), methyl 5-(bromomethyl)picolinate (0.350 g; 0.230 mmol), tetrakis-(triphenylphosphine)-palladium(0) (0.175; 0.152 mmol) and N,N diisopropylethylamine (0.524 g; 3.04 mmol) in dimethoxyethane (9 mL) and water (3 mL) was irradiated in a microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichlomethane) to afford 0.149 g (40%) of the title compound as a yellow oil.
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C>C1COCC1.ClCCl>[C:2]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]([NH:18][C:19](=[O:21])[CH3:20])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:1]
Reactant: N#CBr
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.37 g (13.0 mmol) Cyanogen bromide are added to a mixture of 2.0 g (8.12 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 4.86 mL (28.4 mmol) DIPEA in 15 mL THF and 15 mL dichloromethane. The mixture is stirred for 4 h at rt. After that time, the solvents are removed in vacuo. The residue is taken up in ethylacetate, the mixture is washed with water and the organic layer is concentrated. After addition of diethyl ether the precipitate is collected by filtration, followed by washing with diethylether to yield the desired product.
Reaction SMILES: [Al].O.[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[C:21]([CH:27]=[C:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:20][CH:19]=1>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[C:21]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:20][CH:19]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Agent: [Al]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 50 °C

Procedure:
10 g activated aluminium needles and 1 ml water are added to a solution of 2.03 g (4.3 mmol) 5-{4-[2-(5-Methyl-2-phenyloxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethylidene}-thiazolidine-2,4-dione (Fp. 204-207° C.) in 130 ml tetrahydrofuran. Then it is heated for 50 min. while stirring to 50° C. and the solid components are removed by filtration. The filtrate is evaporated and the residue is chromatographed on silica gel with a mixture of 88 parts by volume toluene, 10 parts by volume 2-butanone and 2 parts by volume glacial acetic acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:18])[O:4]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:18])[O:4][C@H:3]1[CH2:2][NH:1][C:26]([NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])([OH:17])=[O:16]
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CN)O1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CNC(=O)Nc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-aminomethyl-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (50 mg) in pyridine (0.5 ml) was added phenylisocyanate (0.1 ml) and stirred at room temperature for 1 hour. To this mixture water (1 ml) was added and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1N hydrochloric acid. The organic layer was evaporated in vacuo and the crude residue was purified with preparative TLC to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(3-phenylureidomethyl)-1,3-dioxane (27 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[C:19](=O)([O-])[OH:20].[Na+]>CO>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:20][CH3:19])=[O:7]
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cccc(CBr)c1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
3-Bromomethylbenzoyl chloride (1.96 g, 10.37 mmol) was dissolved in methanol (20 ml), and triethylamine (1.5 ml) was added thereto. The mixture was stirred at room temperature for 1 hour. The mixture was poured into a saturated sodium hydrogencarbonate solution and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.90 g, 10.29 mmol, yield: 97%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]([C:8](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10])C(C)=O)(=[O:3])[CH3:2].[CH3:19][O-].[Na+].[H][H].Cl>[Ni].C(OCC)C.CO>[CH3:19][O:11][C:9](=[O:10])[CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: C[O-]
Reactant: CC(=O)N(C(C)=O)C(=Cc1ccccc1)C(=O)O
Agent: [Ni]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)NC(C)=O
Reaction time: 0.17 h
Yield: 9491.4 %

Procedure:
A methanol (24 ml) slurry of the azlactone of N-acetyl-acetaminocinnamic acid (18.7 g, 0.10 mol) was treated with sodium methoxide (0.54 g. 0.01 mol) and the resulting dark solution was stirred for 10 minutes. The solution was then hydrogenated (200 psi hydrogen) over Raney nickel (5.87 g, 0.10 mol) in a sealed Parr autoclave at 50° C. for 2.5 hours. After cooling the reaction mixture was filtered through a Celite pad to remove the nickel, and concentrated in vacuo to afford a red oil which was slurried in diethyl ether (200 ml). The ethereal slurry was shaken with cold hydrochloric acid (0.5N, 100 ml) for approximately one minute. The layers were separated and the aqueous portion was extracted with additional diethyl ether (100 ml). The combined ether extract was washed with brine (100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a reddish oily residue. The residue was titurated in petroleum ether (100 ml) and the solvent was evaporated to give 210 g (95%) N-acetyl-D,L-phenylalanine methyl ester as a light yellow solid which could be recrystallized from diethyl ether-petroleum ether to give a colorless solid. The melting point was 62°-63° C. The proton NMR agreed with the conclusion that N-acetyl-D,L-phenylalanine methyl ester was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].O>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:18]
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(N=c1cccc[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
25 g (270 mmol) of 2-aminopyridine was dissolved in 200 ml of anhydrous dichloromethane, 41 ml (30 g, 300 mmol) of triethylamine was added thereto, and the mixture was cooled to 0° C. 38 ml (57 g, 270 mmol) of anhydrous trifluoroacetic acid was added dropwise thereto over 15 minutes, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was injected into about 100 ml of iced water, and the mixture was stirred for 10 minutes. The mixture was transferred to a separatory funnel to perform liquid separation, and the organic layer was washed twice with 150 ml of water and twice with 150 ml of a 1% HCl aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 36 g (yield 71%) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:40])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][NH:9][CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])[C:12]2[C:23]([CH3:31])=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:11]1=2.[CH3:41][N:42](C)C=O.N#CBr>CS(C)=O.C(OCC)(=O)C.O>[F:40][C:4]([F:3])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:34]=1)[CH2:8][N:9]([C:41]#[N:42])[CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][CH:20]([CH3:21])[CH3:22])=[O:18])[C:12]2[C:23]([CH3:31])=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:11]1=2
Reactant: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C(F)(F)F)ccc2c1N(C(=O)OC(C)C)CCCC2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) in dry dimethyl sulfoxide (3 mL), add isopropyl 5-(3,5-bistrifluoromethyl-benzylamino)-9-methyl-8-trifluormethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (300 mg, 0.54 mmol) and dry dimethylformamide (2 mL). Add cyanogen bromide (176 mg, 1.62 mmol) and stir the reaction mixture at room temperature overnight. Add sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) and cyanogen bromide (176 mg, 1.62 mmol) and stir at room temperature for one hour. Add additional sodium hydride 60% in mineral oil (32 mg, 0.81 mmol) and cyanogen bromide (176 mg, 1.62 mmol) and stir one hour. Add water and ethyl acetate. Separate the layers and dry the organic phase over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the titled compound (124 mg, 40%). MS (ES+): 582 (M+H).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][NH:21][C:22]=2[CH3:23])=[CH:9]1)=O)(C)(C)C.[N:25]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[C:26]=[O:27].C(O)(=O)C>ClCCl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][NH:25][C:26]([N:21]2[C:22]([CH3:23])=[C:18]([CH2:17][C:10]3[C:11]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:8][CH:9]=3)[C:19]([CH3:24])=[N:20]2)=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(CN=C=O)cc1
Reactant: Cc1n[nH]c(C)c1Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CNC(=O)n2nc(C)c(Cc3c[nH]c4ncccc34)c2C)cc1
Reaction time: 0.5 h

Procedure:
3-(3,5-dimethyl-1H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (514, 10 mg, 0.03 mmol) was dissolved in dichloromethane (0.5 mL). 1,8-Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. 1-Isocyanatomethyl-4-methoxy-benzene (545, 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the reaction. The solvents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0.2 mL) and purified by reverse phase HPLC on a Phenomenex column (50 mm×10 mm ID), eluting with water with 0.1% trifluoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0135. MS (ESI) [M+H+]+=390.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9].Cl.[CH3:30][N:31](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN>ClCCl.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:31][CH3:30])=[O:9]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNC(=O)C(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 3-[2,3-Dimethoxy-6-(1-oxo-indan-4-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 199) (30 mg, 0.078 mmol) in dichloromethane, were added 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (22 mg, 0.117 mmol), 1-Hydroxybenzotriazole hydrate (HOBT) (23 mg, 0.156 mmol) and triethylamine (0.1 mL, 0.234 mmolo) and 1M methylamine solution (0.15 mL, 0.156 mmol) and the resultant reaction mixture was stirred at 16 h at RT. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica gel, 0-60% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[C:4]([CH3:10])[CH:3]=1.[CH:11](=O)[CH2:12][CH3:13]>C(O)C.Cl.[Cl-].[Cl-].[Zn+2]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:10])[CH:3]=1)[NH:8][CH:11]=[C:12]2[CH3:13]
Reactant: CCC=O
Reactant: Cc1cc(Br)ccc1NN
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1c[nH]c2c(C)cc(Br)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 19.8 %

Procedure:
To a suspenstion of (4-bromo-2-methylphenyl)hydrazine (1.44 g, 7.16 mmol) in ethanol (10 mL) was added propionaldehyde (0.68 mL, 9.3 mmol). The solution became clear and the mixture was stirred at room temperature for 45 minutes. The solvents were removed and anhydrous ZnCl2 (1.07 g, 7.88 mmol) was added and the mixture was heated at 170° C. for 30 minutes. The mixture was cooled to room temperature, diluted with 10% HCl, extracted with CH2Cl2 and the organic extract was dried over MgSO4. After filtration and concentration, the residue was purified by CombiFlash (0-10% EtOAc/heptane) to provide 5-bromo-3,7-dimethyl-1H-indole (317 mg, 20%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.N1C2C(=CC=CC=2)C=NC=1>O1CCOCC1>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: c1ccc2c(c1)CCN2
Agent: c1ccc2ncncc2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Ic1ccc2ncnc(N3CCc4ccccc43)c2c1
Yield: 85 %

Procedure:
0.60 g of 4-chloro-6-iodoquinazoline, 0.31 ml of 2,3-dihydro-1H-indole and 0.50 ml of triethylamine in 5.00 ml of dioxane are heated at 80° C. in a flask until the quinazoline has reacted completely (HPLC check, about 24 hours). The cooled reaction solution is evaporated to dryness in a rotary evaporator. The residue is purified by means of column chromatography (gradient EA: methanol 0-20% in 16 min.), giving 0.60 g of 4-(2,3-dihydroindol-1-yl)-6-iodoquinazoline as yellowish solid (yield 85%, content 97%); MS-FAB (M+H+)=373.8; Rf (polar method): 2.21 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=2
Reactant: O=[N+]([O-])O
Reactant: CNc1c2c(nc3ccccc13)CCCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Yield: 47 %

Procedure:
In 100 ml of concentrated H2SO4 at 0° C. was added 4.83 g of 3,4-dihydro-9-(methylamino)acridin-1(2H)-one. While maintaining the reaction at 0° C., 1.92 ml (1 eq) of concentrated HNO3 (70 wt %) was added dropwise over 10 minutes. Since the reaction appeared complete after the addition based on thin layer chromatography, the reaction mixture was poured into ice and neutralized with 50% NaOH. At the basic point a precipitate formed. This was filtered and chromatographed on silica gel (EtOAc) and the product was recrystallized from diichloromethane/hexanes to yield 2.75 g (47%) of a solid, melting point 208° C.