Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=[C:14]([CH3:18])[C:15]([OH:17])=[O:16])([O-:9])=[O:8]>C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=[C:14]([CH3:18])[C:15]([O:17][C:10]1[CH:11]=[CH:12][CH:19]=[CH:20][CH:21]=1)=[O:16])([O-:9])=[O:8]
Reactant: CC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 20.7 g of m-nitro-α-methylcinnamic acid suspended in 300 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction, the solvent was removed by distillation under reduced pressure, upon which m-nitro-α-methylcinnamoyl chloride precipitated. This was dissolved in 300 ml of ethyl acetate, and 9.4 g of phenol was added to the solution. The solution was subjected to reaction at room temperature for 1 hour. Then the reaction mixture was washed with 10% HCL, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to obtain phenyl m-nitro-α-methylcinnamate in the form of a light yellow oily matter. Yield: 25.5 g (90%); IR (cm-1); 1720, 1525, 1352.
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=5)[CH:25]=4)[CH:20]=[CH:19]3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH3:44])=[C:35]=[O:36].[OH-].[Na+].CO>C1COCC1.O.C(OCC)(=O)C>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[CH:28]=[C:29]([NH:33][C:35]([NH:34][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[O:43][CH3:44])=[O:36])[CH:30]=[CH:31][CH:32]=4)[CH:25]=3)[CH:20]=[CH:19]2)=[N:16][CH:15]=1
Reactant: COc1ccccc1N=C=O
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-n3ccc4ccc(-c5cccc(N)c5)cc43)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccccc1NC(=O)Nc1cccc(-c2ccc3ccn(-c4ncnc5[nH]ccc45)c3c2)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
(4-(6-(3-Aminophenyl)-1H-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (30 mg, 0.068 mmol) was dissolved in THF (1 mL). At room temperature, 1-isocyanato-2-methoxybenzene (32.6 μL, 0.25 mmol) was added. The reaction mixture was stirred at 50° C. for 3 hours and cooled to room temperature. After adding 1 N NaOH (1 mL) and MeOH (1 mL), the mixture solution was stirred at room temperature for 2 hours. After adding ethyl acetate and water, the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, DCM:MeOH=20:1) yielded 1-(3-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-indol-6-yl)phenyl)-3-(2-methoxyphenyl)urea (24.3 mg, 0.051 mmol) as white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:23][N:22]([CH:19]1[CH2:18][CH2:17][N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][CH2:20]1)[CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(=O)CC1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Product: CN1CCC(N(C)C2CCN(Cc3ccccc3)CC2)CC1
Yield: 66 %

Procedure:
In operating analogously to preparation LXXI, starting with N-methyl-4-piperidinone and 1-benzyl-4-(methylamino)piperidine, the product sought after is obtained as a yellow oil (yield=66%).
Reaction SMILES: C([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])[CH2:6]1)(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[SH:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[O:29])[CH2:6]1
Reactant: CC(=O)S[C@H]1C[C@@H](COCCNC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)NCCOC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (1.01 g) in methanol (20 ml) was added sodium methoxide (28% solution in methanol) (0.5 ml) at -15°-10° C. in a nitrogen stream and the mixture was stirred at the same condition for 1.5 hours. To the mixture was added glacial acetic acid (0.17 ml) at -10°-0° C. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4S)-4-mercapto- 1-(4-nitrobenzyloxycarbonyl)-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (0.74 g).
Reaction SMILES: S(=O)(=O)(O)O.C=O.[C:8]([O-:11])(=[O:10])[CH3:9].[Na+].[C:13]([O:16][C:17](=O)C)(=[O:15])[CH3:14]>>[C:8]([O:11][CH2:17][O:16][C:13](=[O:15])[CH3:14])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)OCOC(C)=O
Temperature: 150 °C
Reaction time: 3 h
Yield: 2856.3 %

Procedure:
5 g of concentrated sulphuric acid are added dropwise to a suspension of 300 g of paraformaldehyde in 1,020 g of acetic anhydride in the course of 5 minutes, during which the temperature rises from room temperature to about 100° C. When the addition had ended, the mixture is heated to 150° C. and is stirred at this temperature for 3 hours. It is then cooled to room temperature, 25 g of sodium acetate are added and the volatile constituents are distilled off in vacuo. About 1,300 g of distillate are thereby obtained, and are then fractionated, with addition of 10 g of sodium acetate, over a 50 cm packed column. 1,150 g (87.1% of theory) of methylene diacetate of boiling point 96° to 99° C. under 90 mbar are thereby obtained.
Reaction SMILES: CO[C:3]1[C:7](OC)=[CH:6][S:5][CH:4]=1.[CH3:10][CH:11]([OH:16])[CH2:12][CH:13]([OH:15])[CH3:14].C(C1C=CC=CC=1S(O)(=O)=O)CCCCCCCCCCC>C(Cl)(Cl)Cl>[CH3:10][CH:11]1[O:16][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:15][CH:13]([CH3:14])[CH2:12]1
Reactant: CC(O)CC(C)O
Reactant: COc1cscc1OC
Agent: CCCCCCCCCCCCc1ccccc1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Product: CC1CC(C)Oc2cscc2O1
Temperature: 100 °C
Reaction time: 120 h

Procedure:
A three-neck round bottom flask is vacuum dried, fitted with a stir bar, thermometer, and drying tube and maintained under nitrogen. About 500 milliliters (ml) of anhydrous xylene is cannulated into the flask. Two ml of 3,4-dimethoxy thiophene 1 (DMOT) (0.0166 mol), 4.85 ml of 2,4-pentanediol 2 (0.0332), and 0.61 ml of catalyst dodecylbenzene sulfonic acid (DBSA) (0.0025 mol) are added to the flask sequentially with previously degassed disposable syringes through the rubber septa fitted on one of the necks of the flask. The molar proportion between DMOT:diol:DBSA is 1.00:2.00:0.15. The reaction is set to run for five days under stirring at a temperature of around 100° C. The reaction is monitored on a daily basis by gas chromatography-mass spectrometry (GC-MS). After five days, the reaction is cooled to ambient temperature and filtered to remove any solid particulates. The xylene is stripped using a rotary evaporator to result in a green oil. The oil is taken up in a small amount of chloroform and extracted with water three times using sodium chloride to break any emulsion. The chloroform is stripped leaving a green oil. The crude mixture is purified by column chromatography using 70:30 toluene:n-hexane as the eluting solvent. The first fractions contain the product 2,4-dimethyl-3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepine 3 (aDM-ProDOT) and subsequent fractions contain DMOT 1 starting material. The aDM-ProDOT 3 is isolated as a white solid that is dried under vacuum. The final product was confirmed by GC-MS and 1H-NMR.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])[NH2:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:3]2[N:4]([N:13]=[N:2][N:1]=2)[N:5]=1
Reactant: O=N[O-]
Reactant: NNc1nnc(Cl)cc1C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Cl)nn2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To an ice-cold suspension of 3-hydrazino-4-carboxy-6-chloro-pyridazine (1.88 g; 0.01 mole) in 15% acetic acid, a solution of sodium nitrite (0.70 g) in water (5 ml) was added dropwise. After stirring for one hour at 5°-10° C. the separated precipitate was filtered, washed with anhydrous ethanol. The solid was suspended in 2 N HCl, the mixture was stirred for 30 minutes, the solid was stirred off, washed with cold water and dried under vacuum at 70° C. to give 1.73 g (87%) of the title compound, m.p. 225° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:7])[OH:6].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][PH:5](=[O:6])[OH:7])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC[PH](=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCC[PH](=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g of 3-aminopropylphosphinic acid in 200 ml of water is cooled to 5°, and the pH adjusted to 9.5 with 2 molar sodium hydroxide solution. To this mixture is added 6.8 g of benzyl chloroformate whilst maintaining the pH and temperature. After the addition is complete the mixture is stirred for 3 hours at pH 9.5 at room temperature and left to stand overnight. The mixture is then extracted with 100 ml of ether and the aqueous layer stirred at 5° with an equal volume of chloroform. The mixture is acidified to pH 2, the chloroform layer separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure. The oily product is triturated with ether to give a white solid, 3-(N-benzyloxycarbonylamino)propylphosphinic acid, m.p. 53°-55°, 31P-NMR: δ=+36.6 ppm (CDCl3).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[C:30]([CH:32]=O)[N:29]=[C:28]2[N:34]=[CH:35][CH:36]=[CH:37][C:27]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[CH2:24][CH2:23][N:22]([CH2:32][C:30]5[N:29]=[C:28]6[N:34]=[CH:35][CH:36]=[CH:37][C:27]6=[N:26][CH:31]=5)[CH2:21][CH2:20]4)[N:14]3[CH:25]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cn3c(N4CCNCC4)cccc3n2)cc1
Reactant: O=Cc1cnc2cccnc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1ccc(-c2cn3c(N4CCN(Cc5cnc6cccnc6n5)CC4)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Crude 2-(4-tert-Butyl-phenyl)-5-piperazin-1-yl-imidazo[1,2-a]pyridine (0.100 g, 0.298 mmol) and pyrido[2,3-b]pyrazine-3-carbaldehyde (0.062 g, 0.378 mmol) was dissolved in NMP (5 mL). The mixture was treated with 3 drops of glacial acetic acid, followed by sodium triacetoxyborohydride (0.126 g, 0.596 mmol.) The mixture was stirred at room temperature overnight and then purified by semipreparative RP-HPLC (Method C) followed by basification as in example 18 to obtain 0.0155 g of the title compound (11%). HPLC (Method B): r.t.=9.0 min., purity 85.2% at 210-370 nm, 81.1% at 252 nm. HRMS: calcd for C29H31N7+H+, 478.27137; found (ESI, [M+H]+), 478.271.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5]C=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29](O)=[O:30])=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:8]1([CH2:9][NH:10][C:29]([C:26]2[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:30])[CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCC1CCCC1)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.03 (bs, 1H), 8.95 (t, J=6.1 Hz, 1H), 8.62 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.29 (d, J=9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.1 Hz, 1H), 4.99-4.75 (m, 4H), 3.28-3.20 (m, 2H), 2.31-2.13 (m, 1H), 1.75-1.38 (m, 6H), 1.39-1.18 (m, 2H); MS (ESI(+)) m/e 367 (M+H)+.
Reaction SMILES: [N+]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[CH2:14][C:15]#[N:16])([O-])=O.O.C(O)(=O)C>CCO.[Pd]>[F:13][C:10]([F:11])([F:12])[C:8]1[CH:9]=[C:4]2[C:5]([CH:14]=[CH:15][NH:16]2)=[CH:6][CH:7]=1
Reactant: N#CCc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: FC(F)(F)c1ccc2cc[nH]c2c1
Yield: 114.6 %

Procedure:
The commercially available (2-nitro-4-trifluoromethylphenyl) acetonitrile (14.0 g, 60.8 mmol) was dissolved in 9:1 EtOH:H2O (50 mL) and glacial acetic acid (1.4 mL). This mixture was hydrogenated over 10% Pd/C (5.0 g) at 50 psi for 16 h at room temperature. The reaction was filtered over celite and evaporated in vacuo. The residue was partitioned between saturated aqueous sodium carbonate and dichloromethane (2×200 mL) and the combined organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (hexanes/ethyl acetate, 20:1, 9:1, 5:1) to afford 12.9 g (65% yield) of 6-trifluoromethyl-1H-indole as a yellow solid: 1H NMR (400 MHz, CDCl3) 8.36, (1H, br s), 7.72 (2H, m), 7.37 (2H, m), 6.63 (1H, m); MS m/e 184 (M−H)−. Anal calcd. for C9H6F3N: C, 58.38; H, 3.26; N, 7.56. Found: C, 58.30; H, 2.92; N, 7.49.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:41]([CH3:42])=[CH:40][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH:19]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([CH3:39])[N:34]=[CH:33]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl.CC(O)C>>[C:1]([O:5][C@@H:6]([C:10]1[C:41]([CH3:42])=[CH:40][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH:19]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[N:35]([CH3:39])[N:34]=[CH:33]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:43]1[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(N3CCN(C(=O)OC(C)(C)C)C(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reaction time: 24 h

Procedure:
To (2S)-2-tert-butoxy-2-(2-(4-(tert-butoxycarbonyl)-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)acetic acid (4 mg) was added hydrochloric acid in 2-propanol (3 mL, 0.5 N, 1.5 mmol). The mixture was stirred for 24 hours. Concentration and purification with reverse phase HPLC gave (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C32H35ClN5O3S: 604.2 (M+H+); Found: 604.3 (M+H+). 1H-NMR 400 MHz, (CD3OD) δ 8.10 (s, 1H), 7.97 (s, 1H), 7.72 (m, 1H), 7.6-7.4 (m, 5H), 7.38 (s, 1H), 5.15 (s, 1H), 4.7 (m, 1H), 4.45 (m, 1H), 4.26 (m, 1H), 4.11 (s, 3H), 3.8 (m, 1H), 3.65-3.4 (m, 3H), 2.50 (s, 3H), 0.94 (s, 9H);
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCCl>[O:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8]1
Reactant: O=C(Cl)CCCOc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1CCCOc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 238 g (1.2 mole) of 4-phenoxybutyryl chloride, dissolved in 350 ml of 1,2-dichloroethane, is added dropwise to a suspension, cooled to 0° C., of 192 g of aluminum trichloride in 1,200 ml of 1,2-dichloroethane within 4.5 hours while passing through nitrogen and stirring vigorously. The mixture is then stirred at 0° C. for 1.5 hours and allowed to warm to room temperature overnight. The mixture is added to a stirred mixture of 2,000 ml of concentrated hydrochloric acid and 2.5 kg of ice and then stirred for 1.5 hours. The aqueous phase is decanted off, and insoluble residue is removed from the organic phase by filtration, washing thoroughly with 1,2-dichloroethane. The aqueous phase is extracted 3-4 times more with methylene chloride, and the combined organic phases are washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution and dried over sodium sulfate. A yellowish oil is obtained after the solvent has been evaporated off in vacuo and is dissolved in diethyl ether, and the last residues of dyestuff are removed by filtration. Evaporation in vacuo results in a clear oil which distils at 74°-75° C./0.02 torr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29](F)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C1(C(N2CCC(OC3C=CC(NC4C5C=C(N6CCCC6)N=CC=5N=CN=4)=CC=3C)CC2)=O)CCCC1>>[C:1]([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:22]4[CH:30]=[C:29]([N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[N:28]=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:16][C:15]=2[CH3:32])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Agent: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1

Procedure:
The Title compound was prepared from 3-[4-(6-Fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-benzoic acid tert-butyl ester and pyrrolidine by a procedure analogous to that described for the synthesis of Cyclopentyl-{4-[2-methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-piperidin-1-yl}-methanone. LRMS: 498.3 (MH+). 1H NMR (DMSO-d6, 400 MHz): δ 9.60 (s, 1H), δ 8.76 (s, 1H), δ 8.31 (s, 1H), δ 7.73-7.76 (m, 2H), δ 7.56-7.58 (m, 1H), δ 7.45 (t, J=7.89, 1H), δ 7.31-7.32 (m, 1H), δ 7.13-7.16 (m, 1H), δ 7.09 (s, 1H), 7.01 (d, J=9.14, 1H), δ 3.45-3.48 (m, 4H), δ 2.15 (s, 3H), δ 1.97-2.01 (m, 4H), δ 1.48 (s, 9H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:23])[C:16]1C=[CH:20][CH:19]=[CH:18][C:17]=1O.Cl>N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:15](=[O:23])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[O:4][C:2]1=[O:3]
Reactant: COC(=O)Cl
Reactant: O=C(Nc1ccc(F)cc1F)c1ccccc1O
Agent: Cl
Solvent: c1ccncc1
Product: O=c1oc2ccccc2c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl chloroformate (0.1 mL, 1.2 mmole) was added dropwise to a stirred solution of compound 3a (0.50 g, 2 mmole) in dry pyridine (8 mL) at 0° C. The mixture was refluxed for 2 hr. After 16 hr stirring at room temperature, the pH of the reaction mixture was adjusted to pH=6 from 1 M HCl(aq). The resulting white mixture was cooled to obtain solid compound. The product was filtered off and recrystallized from hot ethanol.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Br[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH3:31]>CN(C)C=O.O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:23]=[CH:22][C:21]=2[O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: COc1ccc(C(C)(C)C)cc1CBr
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cc(C(C)(C)C)ccc1OC
Yield: 93.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.154 g, 3.85 mmol) was added to a solution of 5-chloro-1H indole-2-carboxylic acid ethyl ester (0.70 g, 3.14 mmol) in dimethyl formamide (8 ml) with stirring under nitrogen, followed after 1 h by 2-bromomethyl-4-tert-butyl-1-methoxybenzene (1.00 g, 3.89 mmol). After stirring for 17 h, the reaction was diluted with water (15 ml), extracted into ethyl acetate (2×30 ml), washed with water (2×30 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification was achieved by chromatography on silica using DCM as eluent to yield 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid ethyl ester as an off-white solid (1.18 g, 2.95 mmol, 94%).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:15]2[C:10]([C:11]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:12]=3[CH2:13][CH2:14]2)=[N:9]1)=[O:7])(=O)C.[OH-].[Na+]>CO.C(OCC)(=O)C>[OH:4][CH2:5][C:6]([N:8]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:15]2[C:10]([C:11]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:12]=3[CH2:13][CH2:14]2)=[N:9]1)=[O:7]
Reactant: COc1ccc([C@H]2[C@H]3CCc4ccc(OC)cc4C3=NN2C(=O)COC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2[C@H]3CCc4ccc(OC)cc4C3=NN2C(=O)CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a solution 150 (0.150 g, 0.36 mmol) in methanol (10 mL) was added NaOH (50%, 2 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h before being diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel column using ethyl acetate-hexane (2:3) as eluent to furnish (151) (0.105 g, 78%): mp 163-64° C., 1H NMR (400 MHz, CDCl3): δ 1.06-1.17 (m, 1H), 1.72-1.78 (m, 1H), 2.76-2.89 (m, 2H), 3.76 (s, 3H), 3.87 (s, 3H), 4.55-7.70 (m, 2H), 5.66 (d, J=10.0 Hz, 1H), 6.82 (d, J=9.2 Hz, 2H), 6.92-6.95 (dd, J=2.4 and 8.8 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ 24.38, 28.90, 48.57, 55.46, 55.76, 61.40, 69.61, 108.02, 114.34, 119.12, 127.53, 127.84, 128.47, 130.32, 132.61, 157.67, 158.36, 159.42, 168.66. Anal. (C21H22N2O4) C, H, N.