Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C:16]([CH3:23])([CH3:22])[C:17]([O:19]CC)=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:1]([N:4]([C:16]([CH3:23])([CH3:22])[C:17]([OH:19])=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CCN(NC(=O)NCc1ccccc1)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of ethyl 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)-2-methylpropanoate (Compound V-1) (958.2 mg, 3.0 mmol) in tetrahydrofuran/methanol/water (2:3:1, 15 ml), lithium hydroxide monohydrate (251.8 mg, 6.0 mmol) was added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water (25 ml) and washed with ether (25 ml). The aqueous layer was acidified with 10%-citric acid (15 ml) and extracted with chloroform (30 ml). The organic layer was washed with brine (25 ml) and dried over magnesium sulfate and then filtered. The filtrate was concentrated in vacuo to obtain the title compound (724 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:22][C@H:21]([CH2:23][O:24]C4CCCCO4)[C@@H:13]([O:14]C4CCCCO4)[C@H:12]3[F:31])[C:6]=2[N:7]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[NH2:1][C:2]1[N:3]=[C:4]([Cl:32])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:13]([OH:14])[C@H:12]3[F:31])[C:6]=2[N:7]=1
Reactant: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](COC4CCCCO4)[C@@H](OC4CCCCO4)[C@H]3F)c2n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Nc1nc(Cl)c2ccn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3F)c2n1
Yield: 99.1 %

Procedure:
A solution of the compound from Step H (40 mg. 0.08 mmol) in EtOH (2 mL) was stirred with pyridinium p-toluenesulfonate (40 mg, 0.16 mmol) at 60° C. for 3 h. The mixture was then evaporated and the residue purified on a silica gel column with a solvent system of hexanes/EtOAc:1/1 and 1/2 to give the desired compound (24 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH2:51])[C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:39][O:40][C:41](=[O:52])[CH:42]([NH:51][C:10](=[O:11])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: COC(=O)C(N)C(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)C(NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid (5.49 g; 17.42 mmol) was dissolved in dry tetrahydrofuran (200 ml) and N-methylmorpholine (1.92 ml; 17.42 mmol) was added. The reaction mixture was cooled to -20° C. and stirred 15 min. Isobutyl chloroformate (2.27 ml; 17.42 mmol) was dissolved in dry tetrahydrofuran (3 ml) and added dropwise to the reaction mixture at -20° C. N-methylmorpholine (1.92 ml; 17.42 mmol) and 2-amino-3-oxo-3-phenylpropionic acid methylester (4.0 g; 17.42 mmol) were added and and the mixture was stirred 30 min at -20° C. The reaction mixture was heated to room temperature and the solvent was removed in vacuo. The residue was dissolved in methylene chloride (200 ml), washed with water (200 ml) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (5×45 cm) using heptane/ethyl acetate/methylene chloride (2:1:1) as eluent to afford 6.19 g of a diastereomeric mixture of 2-((2R)-2-tert-butoxycarbonylamino-3-(2-naphthyl)propionylamino)-3-oxo-3-phenylpropionic acid methylester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Br[C:14]1[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=1>>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17](/[C:20](/[CH3:24])=[CH:21]/[CH2:22][OH:23])=[CH:16][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Product: CC(=O)c1cccc(-c2ccc(/C(C)=C/CO)cc2)c1

Procedure:
3-Acetylphenylboronic acid (7.10 g, 43.3 mmol) was coupled with (E)-3-(4-bromophenyl)-but-2-en-1-ol (5.76 g, 25.0 mmol) by a procedure analogous to that described in example 54a to give (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an off-white solid; 5.33 g (79%). This solid was recrystallised from aqueous ethanol to give a first crop of very pure (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as colourless platelets; 2.78 g (41%) and a second crop of (E)-3-(3′-acetyl-biphenyl-4-yl)-but-2-en-1-ol as an amorphous off-white solid; 2.53 g (37%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[F:11])=[O:3].[BH4-].[Na+].[OH-].[Na+].Cl>C(O)(C)C.O>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([F:11])[C:4]=1[CH:2]([OH:3])[CH3:1]
Reactant: CC(=O)c1c(F)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(O)c1c(F)cccc1Cl
Reaction time: 1 h

Procedure:
2-chloro-6-fluoroacetophenone of (A) (45.0 g, 0.26 mol) is dissolved in isopropyl alcohol (98 ml) and NaBH4 (4.9 g, 0.13 mol) is added. The resultant mixture is warmed to 55° C. for about 16 hours. A solution of NaOH 10.4 g, 0.26 mol) in water (41. ml) is then added. After 1 hour at 55° C., this reaction mixture is cooled and acidified with diluted HCl. Extraction with chloroform provided pure title product (45.1 g, 99.1%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:10][C:9]=2[N+:20]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[CH:1]1([NH:7][C:8]2[C:9]([NH2:20])=[CH:10][C:11]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1cc(Cn2ccnc2)ccc1NC1CCCCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cc(Cn2ccnc2)ccc1NC1CCCCC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A mixture of 7.9 parts of N-cyclohexyl-4-(1H-imidazol-1-ylmethyl)-2-nitrobenzenamine, 22.9 parts of sodium dithionite, 288 parts of ethanol and 240 parts of water was stirred at room temperature. Upon complete reaction, the ethanol layer was evaporated. The aqueous layer was diluted with a potassium carbonate solution. The whole was extracted twice: first with dichloromethane and then with a mixture of trichloromethane and methanol (90:10 by volume). The combined extracts were dried, filtered and evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again, yielding 7 parts (98.0%) of was evaporated again, yielding 7 parts (98.0%) of N1 -cyclohexyl-4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine as a residue (int. 186).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].COCCOC.Br[C:25]1[C:26]([C:39]#[N:40])=[N:27][N:28]([CH2:35][CH2:36][O:37][CH3:38])[C:29]=1[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34]>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.O>[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:25]1[C:26]([C:39]#[N:40])=[N:27][N:28]([CH2:35][CH2:36][O:37][CH3:38])[C:29]=1[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34]
Reactant: COCCn1nc(C#N)c(Br)c1CCCCCl
Reactant: Nc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COCCn1nc(C#N)c(-c2ccccc2N)c1CCCCCl
Temperature: 110 °C
Yield: 57.8 %

Procedure:
2-Aminophenylboronic acid hydrochloride (16.2 g, 93.5 mmol), potassium carbonate (42.5 g, 308 mmol), DME (333 mL), water (166 mL), and 4-bromo-5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile (30 g, 93.5 mmol) were combined in a flask, which was then evacuated three times and filled with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (0.65 g, 0.94 mmol) was then added, and the reaction was heated at 110° C. for one hour. An analysis by HPLC indicated the presence of starting material, and additional 2-aminophenylboronic acid hydrochloride (16.2 g, 93.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.65 g, 0.94 mmol) were added. The reaction was then heated at reflux overnight and allowed to cool to ambient temperature. Water (30 mL) was added, and the mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting sequentially with 25% ethyl acetate in hexanes and 75% ethyl acetate in hexanes) to provide 18 g of 4-(2-aminophenyl)-5-(4-chlorobutyl)-1-(2-methoxyethyl)-1H-pyrazole-3-carbonitrile as a maroon oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2C=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([F:20])[C:14]=2[OH:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cc(F)c2C=O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)cc(F)c2O)C1
Reaction time: 72 h
Yield: 45.6 %

Procedure:
To a solution of the title compound of Step B (650 mg, 2.0 mmol) in CH2Cl2 (100 mL) was added 77% m-CPBA (510 mg, 3.0 mmol). After stirring for 72 h, the starting aldehyde remained as determined by analytical HPLC analysis. Thus an additional portion of m-CPBA (790 mg, 4.6 mmol) was added. After 18 h, analytical HPLC analysis indicated that the reaction was complete. A solution of 10% aqueous sodium bisulfite (100 mL) was added to the reaction mixture. After an additional 18 h, CH2Cl2 was added and the aqueous portion extracted three times with CH2Cl2. The combined organic extracts were washed with saturated NaHCO3 (2×) and concentrated. The residue was then treated with MeOH (500 mL) and 1 N NaOH (250 mL). The solution immediately turned dark brown. After 2 h, the MeOH was removed by rotary evaporation and 1 M KHSO4 was added to the residue until the pH of the solution reached pH=4. The reaction mixture was then extracted with EtOAc (3×). The combined organic layers were washed with brine and dried. The residue was purified by RP HPLC to provide the desired phenol (290 mg, 46%). 1H NMR (CDCl3): 6.74 (dd, J=10.1, 2.3 Hz, 1H), 6.30 (dd, J=2.0, 2.1 Hz, 1H), 4.87-4.80 (m, 1H), 4.26 (dd, J=9.9, 6.4 Hz, 2H), 4.00 (dd, J=9.9, 3.8 Hz, 2H), 3.29-3.13 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=3[CH3:22])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])[CH:3]=1.Cl.[CH3:32][O:33][C@H:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1([CH3:41])[CH3:40].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.C(Cl)Cl.[Cl-].[Na+].O>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[C:4]1[CH:3]=[C:2]([N:37]2[CH2:38][CH2:39][C@H:34]([O:33][CH3:32])[C:35]([CH3:41])([CH3:40])[CH2:36]2)[C:11]2[C:10](=[O:12])[N:9]([C:13]3[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=3[CH3:22])[CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)cc(Cl)c2C1=O
Reactant: CO[C@H]1CCNCC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CO[C@H]1CCN(c2cc(-c3c(C)cccc3C)nc3c2C(=O)N(c2cc(C(C)C)ccc2C)CC3)CC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 10-mL reaction flask containing an orange solution of 4-chloro-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (100 mg, 0.239 mmol), (S)-4-methoxy-3,3-dimethylpiperidine HCl salt (129 mg, 0.716 mmol), and DIEA (208 μL, 1.193 mmol) in DMA (1.2 mL) was placed in a sand bath preheated to 110° C. and stirred at that temperature. After 4 h the reaction mixture was allowed to cool to room temperature, then diluted with DCM and poured into mixture of saturated aqueous sodium bicarbonate solution and brine. The aqueous layer was extracted with DCM (3×), and the combined organic layers were washed with brine, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-100% EtOAc/heptane) to provide (S)-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.07-7.25 (m, 6 H) 6.73 (s, 1 H) 3.80-3.96 (m, 1 H) 3.63-3.79 (m, 1 H) 3.27 (s, 3 H) 3.09-3.24 (m, 2 H) 2.93-3.07 (m, 3 H) 2.79-2.92 (m, 2 H) 2.18-2.22 (m, 3 H) 2.06 (s, 6 H) 1.79-1.94 (m, 1 H) 1.48-1.65 (m, 1 H) 1.21 (d, J=6.8 Hz, 6 H) 1.14-1.19 (m, 1 H) 0.90 (s, 3 H) 0.83 (s, 1 H)* 0.78 (s, 2 H)*; MS (ESI+) m/z 526.3 (M+H)+. (*indicates one methyl group appearing as two peaks due to restricted rotation).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][C:31]([CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1>>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][C:31]([C:35]2([CH2:5][OH:16])[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]([CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:36]2=[O:49])=[C:30]([OH:50])[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc(Cl)c(Cl)cc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(Cl)c(Cl)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(4,5-dichloro-2-hydroxyphenyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 376 (M−17), 416 (M+23).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:14][CH:15]=2)C=CC=CC=1.C1(OC(Cl)=O)C=CC=CC=1.[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C=O)C>C(Cl)Cl>[CH:22]1([N:19]2[CH2:18][CH2:17][N:16]([C:13]3[N:12]=[CH:11][C:10]([NH:9][C:8]([N:42]4[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]4)=[O:27])=[CH:15][CH:14]=3)[CH2:21][CH2:20]2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC1CCNCC1
Reactant: O=C(Nc1ccc(N2CCN(C3CCCC3)CC2)nc1)Oc1ccccc1
Agent: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)Nc2ccc(N3CCN(C4CCCC4)CC3)nc2)CC1
Yield: 45.8 %

Procedure:
A mixture of 29 mg (0.08 mmol) [6-(4-cyclopentyl-piperazin-1-yl)-pyridin-3-yl]-carbamic acid phenyl ester (intermediately built from intermediate 6 and phenylchloroformate) and 12 mg (0.12 mmol) 4-methyl-piperidine (commercially available) in 1 ml DCM and 0.1 ml DMF was stirred at room temperature for 16 h. After evaporation the residue was taken up in methanol/DMF and subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.05% triethylamine). The combined product fractions were evaporated to dryness to yield 13.6 mg (46%) of the title compound. (m/e): 372.3 (MH+; 100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[OH:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(#N)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][O:17][C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:10])[CH:16]=2)=[CH:4][CH:5]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1.40 g (7.41 mmol) 1-bromomethyl-4-fluoro-benzene in 20 mL acetonitrile is added 822 mg (7.40 mmol) 2,4-dihydroxy pyridine and 2.05 g (14.8 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT. 5 mL of DMF is added and the reaction is stirred overnight. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Br[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][NH:4][CH2:1][CH2:2][CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCCOc1ccccc1
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Product: CCCNCCOc1ccccc1

Procedure:
47.2 g. Propylamine was dissolved in 100 ml. absolute alcohol with cooling and 40.2 g. β-bromophenetole was added portionwise to the solution formed. After completion of the addition the reaction mixture was allowed to stand at room temperature for one week with occasional agitation. The excess of amine and solvent were then removed under vacuum from the steam bath and the residual colourless solid obtained on cooling was treated with an excess of 5N aqueous sodium hydroxide. An oil was liberated which was then extracted with ether, washed with water and dried over anhydrous sodium sulphate. After removal of the solvent the residual oil was distilled under vacuum to give N-2-phenoxyethyl-N-propylamine, boiling point 90°-92° C./0.2 mm.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=3)=[O:22])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Nc1cccc2cnccc12
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc2cnccc12

Procedure:
Prepared from isoquinolin-5-amine and 4-(trifluoromethyl)phenyl isocyanate according to Description 61. m/z (ES+) 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[O:11].[F:12][C:13]1[CH:23]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([NH2:24])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:24][C:16]1[C:17](=[CH:23][C:13]([F:12])=[CH:14][CH:15]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(F)ccc1N
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)ccc1NC(=O)Nc1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A solution of 2,4-dichlorophenyl isocyanate (47.0 g, 0.25 mol) in xylene (130 ml) is metered at room temperature into a solution of ethyl 5-fluoroanthranilate (45.2 g, 0.25 mol) in xylene (210 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. Triethylamine (3.5 ml, 2.55 g, 0.025 mol) is metered in. The mixture is stirred at 90° C. for a further 2 hours. After cooling, the product is filtered off with suction and washed with 3×30 ml of xylene and dried. 86.9 g of ethyl N-(2,4-dichlorophenylcarbamoyl)-5-fluoroanthranilate of melting point 219° to 223° C. (decomposition) are obtained. The cyclization product 3-(2,4-dichlorophenyl)-6-fluoro-2,4(1H,3H)-quinazolinedione cannot be detected by thin-layer chromatography.
Reaction SMILES: [F:1][CH:2]([F:51])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([N:27]4[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:45])[O:34][CH2:35][CH2:36][O:37]CC5C=CC=CC=5)[C:28]4=[O:46])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:47]=[CH:48][CH:49]=[CH:50][C:5]=2[N:4]=1>CO.[C].[Pd]>[F:51][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([N:27]4[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:45])[O:34][CH2:35][CH2:36][OH:37])[C:28]4=[O:46])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:47]=[CH:48][CH:49]=[CH:50][C:5]=2[N:4]=1
Reactant: O=C(N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O)OCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O)OCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(benzyloxy)ethyl {(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (84 mg) in methanol (1 mL) was added 10% palladium-carbon (50% wet) (84 mg), followed by stirring at room temperature overnight at 3 atm under a hydrogen atmosphere. The catalyst was removed and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=100:0-92:8) to obtain 2-hydroxyethyl {(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (30 mg).
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:49]=[CH:50][C:51]([OH:57])=[C:52]([NH:54][CH:55]=[O:56])[CH:53]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C@@H:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][CH2:34][N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH:26]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.CCN(CC)CC.F.F.F.N>O1CCCC1>[NH3:11].[CH:39]([N:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C@@H:32]([C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]([C:48]3[CH:49]=[CH:50][C:51]([OH:57])=[C:52]([NH:54][CH:55]=[O:56])[CH:53]=3)[OH:8])=[CH:19][CH:18]=2)[CH:30]=[CH:29][C:28]=1[OH:31])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Agent: F
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(NC=O)c3)cc2)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-{5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]-2-hydroxyphenyl}formamide (Preparation 30, 280 mg, 0.35 mmol) was dissolved in tetrahydrofuran (5 ml) and triethylaminetrihydrofluoride (0.29 ml, 1.8 mmol) was added, and the mixture stirred overnight at room temperature. Tetrahydrofuran (6 ml) and 880 ammonia (6 ml) were then added, the mixture stirred for 20 minutes, organics were then separated and washed with saturated aqueous sodium hydrogen carbonate (10 ml), then brine (10 ml), then dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98/2/0.2 to 88/12/1.2 by volume) to furnish the title compound as an off-white solid, 74 mg.