Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7]Br)[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:11])([CH3:10])[C:6](=[O:9])[CH2:7][O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[CH3:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)C(=O)COc1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
316 g (2 mol) of 4-bromo-2,2-dimethyl-3-keto-butanoic acid ethyl ester were added dropwise, at 30° C., to 246 g (2 mol) of 4-chlorophenol and 210 g of potassium carbonate in 1,000 ml of dimethylformamide. The mixture was stirred for 20 hours at room temperature and 2 hours at 40° C. The reaction mixture was then introduced into 2,000 ml of water. The aqueous phase was extracted by shaking twice with 500 ml of methylene chloride at a time and the organic phase was extracted by shaking twice with 250 ml of water each time. The combined organic phases were dried, concentrated and distilled. 324 g (56% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester of melting point 125-135° C./0.1 mm Hg were obtained.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH:23]1([NH2:27])[CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O>[CH:23]1([NH:27][C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (1 mL) in was added cyclobutanamine (100 mg, 1.41 mmol) and DIEA (110 mg, 0.85 mmol). The resulting solution was stirred for 2 hours at 70° C., and then quenched by the addition of water (50 mL) and extracted with dichloromethane (4×20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (2%-10% ethyl acetate in petroleum ether) to afford methyl 3-(cyclobutylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (67 mg, 58%)
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[O:16])=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Li]CCCC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[C:1]([N:4]([S:36]([CH3:35])(=[O:38])=[O:37])[C:5]1[C:6]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:22][CH:23]=3)=[O:16])=[CH:13][CH:12]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)N(c1cccnc1-c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1)S(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
The product from Example 5 (610 mg, 1.58 mmol) in tetrahydrofuran (10 mL) was treated with n-BuLi (1.1 mL, 1.6 M in hexanes, 1.76 mmol) dropwise at −10° C. The reaction mixture was stirred at −10° C. for 15 minutes and then treated with methanesulfonyl chloride (0.13 mL, 1.68 mmol). The mixture was allowed to gradually warm to room temperature and stir overnight, quenched with H2O (10 mL), and diluted with ethyl acetate (50 mL). The layers were separated and the organic layer was washed with H2O (2×10 mL) and brine (10 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluant gradient from 99:1 CH2Cl2:CH3OH to 97:3 CH2Cl2:CH3OH) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.81 (dd, J=4.7 Hz, 1.7 Hz, 1H), 8.15 (dd, J=8.2 Hz, 1.7 Hz, 1H), 8.07 (m, 2H), 7.62-7.73 (m, 5H), 7.35-7.40 (m, 2H), 3.30 (s, 3H), 2.01 (s, 3H), 1.29 (s, 9H); MS (ESI+) m/z δ 466 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[CH3:30][NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35].C(N(C(C)C)C(C)C)C.O>CC(N(C)C)=O>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][N:31]([CH3:30])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 104.2 %

Procedure:
To a stirred solution of N-(4-fluoro-2-methoxy-5-nitro-phenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 176, 65 g, 160.28 mmol) and N,N′,N′-trimethylethane-1,2-diamine (19.65 g, 192.3 mmol) in DMA (630 mL) was added N-ethyl-N-isopropyl-propan-2-amine (26.93 g, 208.4 mmol) at r.t. The resulting mixture was stirred at 85° C. for 5-6 h then cooled to r.t. Water (630 mL) was then added and the mixture was stirred for 3-4 h. Solid material was collected by filtration, washed with water (315 mL) and dried at 50° C. for 12 h to give the title compound (79.4 g, 96%) as orange solid; 1H NMR (CDCl3): 2.29 (6H, s) 2.60 (2H, t), 2.93 (3H, s), 3.31 (2H, t), 3.96 (3H, s), 4.00 (3H, s), 6.69 (1H, s), 7.21 (1H, d), 7.30-7.38 (2H, m), 7.43 (1H, d), 7.56 (1H, s), 8.18 (1H, d), 8.30 (1H, s), 8.41 (1H, d), 9.59 (1H, s); m/z: ES+ MH+ 476.23.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH2:31]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])[CH3:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:31]([O:33][C:34](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:41]=1)[CH3:32]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc32)c1
Yield: 29 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 3-ethoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light yellow foam (29%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[CH:9]=1.[Br:17]N1C(=O)CCC1=O>CC(C)=O.CCOC(C)=O>[Br:17][C:9]1[C:10]2[N:11]=[CH:12][N:13]=[CH:14][C:15]=2[NH:16][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccccc1-c1cc2ncncc2[nH]1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1[nH]c2cncnc2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a slurry of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (1.0 g) in acetone (50 mL) was added N-bromosuccinimide (1.0 g). The reaction was stirred at rt for 2 h, until complete conversion was observed by LC-MS. The reaction mixture was diluted with EtOAc (150 mL) and the solid was collected via filtration and washed with EtOAc yielding 820 mg of desired (60% yield). LCMS calculated for C12H7BrFN3 292.1, found 292.23: [M+].
Reaction SMILES: C([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=O)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:64][C:65]1[CH:66]=[CH:67][C:68]2[N:72]=[C:71](C(O)=O)[NH:70][C:69]=2[CH:76]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:71]4[NH:70][C:69]5[CH:76]=[C:65]([Cl:64])[CH:66]=[CH:67][C:68]=5[N:72]=4)=[O:8])[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: O=C(O)c1nc2ccc(Cl)cc2[nH]1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (20 mg, 0.066 mmol) in 1.5 mL of DMF is added TBTU (923.4 mg, 0.073 mmol), diisopropylethylamine (0.013 ml, 0.073 mmol) and 6-chloro-1H-benzoimidazole-2-carboxylic acid (prepared from literature in Eur.J.med.Chem. 1993, 28, 71) (14.3 mg, 0.073 mmol). The resulting mixture is left to stir at room temperature overnight. The crude mixture is directly purified by reverse phase HPLC (10-70% ACN/H2O). The product (30.1 mg, 55%) is isolated as a white powder. C23H22ClN7O3 MS m/z: 480, 481. Anal. cald. for C23H22ClN7O3. 2C2HF3O2: C, 45.81; H, 3.42; N, 13.85. Found C, 45.19; H, 3.59; N, 13.76.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([CH2:21][C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.N1CCCC1>CO>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:7][C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: O=C1Nc2cc(Cl)ccc2C1=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 70 °C
Yield: 71.7 %

Procedure:
5-Chloro-2-(2,2,2-trifluoro-ethoxy)-benzaldehyde (4 g, 16 mmol) and 6-chlorooxindole (2.8 g, 16 mmol) were mixed in anhydrous methanol (20 mL). Then pyrrolidine (1.32 mL, 16 mmol) was added slowly at r.t. The mixture was heated to 70° C. for 3 h and cooled to room temperature. The precipitate was collected by filtration to give title compound as a yellow solid (Yield: 4.45 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].Cl.[Cl:18][C:19]1[C:20]([CH3:27])=[C:21]([NH:25]N)[CH:22]=[CH:23][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:22]3[C:21](=[C:20]([CH3:27])[C:19]([Cl:18])=[CH:24][CH:23]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Reactant: Cc1c(Cl)cccc1NN
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(C)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: 3-(2-Oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-Chloro-2-methyl-phenyl)-hydrazine hydrochloride.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9]([OH:11])=[O:10].[CH3:15]O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][N:14]=1)[C:9]([O:11][CH3:15])=[O:10]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
To a solution of thionyl chloride (15.0 g, 0.127 mol) in 20 mL of toluene was added 2-chloroisonicotinic acid (10.0 g, 0.063 mol) and the reaction was heated at reflux until gas evolution ceased. Then a solution of methanol (7.7 mL, 0.19 mol) in 10 mL of toluene was added at room temperature over 15 min. The reaction mixture was then refluxed for 1 h and then cooled to room temperature. The clear solution was poured into 100 mL of water, basified with 40% NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate filtered. The filtrate was concentrated in vacuo to give 8.2 g (83%) of product as a brown oil which solidified upon standing, mp: 36-37 C.
Reaction SMILES: C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B(OC)(OC)OC.B.CSC.[C:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([Br:40])[CH:39]=1)(=[O:33])[CH3:32].Cl>O1CCCC1>[Br:40][C:38]1[CH:39]=[C:34]([C@H:31]([OH:33])[CH3:32])[CH:35]=[N:36][CH:37]=1
Reactant: CC(=O)c1cncc(Br)c1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@@H](O)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (253 mg, 1 mmol) and trimethyl borate (0.135 mL, 1.2 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 hour after which time borane-methylsulfide complex (10 mL, 2M in tetrahydrofuran, 20 mmol) was added in one portion and the mixture cooled to 0° C. A solution of 3-acetyl-5-bromopyridine (2 g, 10 mmol) in tetrahydrofuran (10 mL) was added dropwise over 2 hours at 0° C. and then the mixture was allowed to warm to room temperature and was stirred overnight. After this time dilute aqueous hydrochloric acid (2M, 90 mL) was added with initial cooling and the mixture was stirred at room temperature for 2 hours. Dimethyl sulfide and tetrahydrofuran were removed under reduced pressure and the resulting yellow solution was basified to pH 11 with aqueous ammonia, extracted with ethyl acetate (3×50 mL) and the extracts washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give (1R)-1-(5-bromopyridin-3-yl)ethanol (1.9 g) in acceptable purity.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1>[C:17]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)N[C@H](C)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.4 %

Procedure:
A solution of 50.0 g (412.6 mmol) of (R)-1-phenylethylamine and 41.75 g (412.6 mmol) of triethylamine in 750 ml of toluene was cooled to 0° C., and 73.85 g (453.9 mmol) of octanoyl chloride was added dropwise thereto. After completion of the addition, the reaction was allowed to proceed at room temperature for 3 hours. The reaction mixture was again cooled to 0° C. and then the reaction was terminated by addition of 200 ml of 10% hydrochloric acid. The toluene phase was separated, washed with 300 ml of a 10% aqueous solution of sodium hydroxide, and dried over anhydrous sodium sulfate. The solvent was then distilled off, and the residue was quantitated by HPLC. Thus was obtained 19.81 g (97%) of the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[O:16]C)([CH3:3])[CH3:2].O>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: COc1c(-c2ccccc2)cccc1C(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)c1cccc(-c2ccccc2)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 94 %

Procedure:
In a flask charged with 2-bromo-6-isopropylanisole (1.98 g, 8.64 mmol), phenylboronic acid (2.10 g, 17.28 mmol), palladium acetate (96 mg, 0.43 mmol), triphenylphosphine (0.225 g, 0.86 mmol) and potassium phosphate (11 g, 51.84 mmol), mixture of water (8 mL) and dimethoxyethane (32 mL) was added, and the resultant mixture was heated under reflux for 12 hours. After cooling to ambient temperature, aqueous ammonium chloride (15 mL) and diethyl ether (30 mL) were charged thereto. The organic layer was isolated, and the residue was extracted with diethyl ether. Combined organic layer was dried over magnesium sulfate, and evaporated to remove the volatiles to obtain 2-isopropyl-6-phenylanisole as grey solid (2 g). The anisole obtained (without further purification) was dissolved in methylene chloride (15 mL), and 12 mL of boron tribromide solution (1 M in methylene chloride) was added dropwise thereto at −78° C. Reaction was carried out for 12 hours while slowly raising the temperature to ambient temperature. When the reaction was completed, mixture of water (15 mL) and diethyl ether (30 mL) was added thereto. After isolating the organic layer, the aqueous layer was extracted with diethyl ether (15 mL×3). The combined organic layer was dried, and evaporated under reduced pressure to remove the volatiles. The residue was purified via silica gel column by using mixed solvent of hexane and methylene chloride to obtain 2-isopropyl-6-phenylphenol (1.72 g) as white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3=[O:36])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:39][N:38]=[N:37][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3=[O:36])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[C:12]([C:14]2[CH:15]=[N:16][O:17][C:18]=2[CH3:19])=[O:13])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]>C(O)C.[OH-].[K+]>[C:15]([C:14](=[C:18]([OH:17])[CH3:19])[C:12]([N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:20])=[O:13])#[N:16]
Reactant: Cc1oncc1C(=O)N(C)c1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)=C(C#N)C(=O)N(C)c1ccc(C(C)(C)C)cc1

Procedure:
N-[4-(1,1-Dimethylethyl)phenyl]-N-methyl-5-methylisoxazol-4-ylcarboxamide (9.8 g) was magnetically stirred in absolute ethanol (200 ml) and 1N potassium hydroxide solution (36 ml). Within 10 minutes a clear solution had resulted.
Reaction SMILES: C(OC(OCC)CC(OCC)OCC)C.[OH-].[Na+].C([O:20][C:21](=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[C:25]([Br:34])[CH:24]=1)C>O>[Br:34][C:25]1[CH:24]=[C:23]([CH2:22][C:21]([OH:35])=[O:20])[CH:28]=[CH:27][C:26]=1[N:29]1[CH:33]=[CH:32][CH:31]=[N:30]1
Reactant: CCOC(=O)Cc1ccc(-n2cccn2)c(Br)c1
Agent: CCOC(CC(OCC)OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(-n2cccn2)c(Br)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
44.5 g (0.164 mole) of 4-acetamido-3-bromophenylacetic acid and 131 ml of 6 N hydrochloric acid are heated to 100° C. for 2 hours. The solution of 4-amino-3-bromophenylacetic acid (which is thus formed) is cooled to -6° C. in an ice-sodium chloride bath, and a solution of 11.7 g (0.17 mole) of sodium nitrite in 130 ml of water is added dropwise thereto at -6° C. Stirring is continued for a further hour at the same temperature, and the thus-prepared solution of the diazonium salt is poured slowly into a solution (which is cooled to -10° C.) of 100 g (0.443 mole) of tin(II) chloride dihydrate in 100 ml of concentrated hydrochloric acid to form 3-bromo-4-hydraziniumphenylacetic acid chloride. Dilution of the latter with 300 ml of water is effected, and 36 ml (0.163 mole) of 1,1,3,3-tetraethoxypropane are added dropwise thereto; stirring is then effected for 4 hours at room temperature. The resulting reaction mixture is rendered alkaline with 35% strength solution of sodium hydroxide and is heated to 100° C. for one hour in order to hydrolyze 3-bromo-4-(pyrazol-1-yl)phenylacetic acid ethyl ester, which is formed simultaneously along with the corresponding free acid. The produced ethanol is distilled off, and clarification is effected with activated charcoal. This is followed by acidification with hydrochloric acid and extraction with chloroform. The organic phase is dried. Concentration to dryness is effected in a vacuum, and the residue is recrystallized from benzene to obtain 38.5 g (83.5% of theory) of 3-bromo-4-(pyrazol-1-yl)phenylacetic acid (m.p. 100° to 101° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:8][C:9]([S:13][CH3:14])=[N:10][C:11]=1[CH3:12])=[O:5])C.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH3:12])[N:10]=[C:9]([S:13][CH3:14])[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1-c1cccc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc(C)c(C(=O)O)c(-c2cccc(Cl)c2)n1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
1.44 g (4.47 mmol) of 4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimidinecarboxylic acid ethylester was dissolved in 10 ml of THF and 5 ml of water. 225 mg (5.36 mmol) of lithium hydroxide monohydrate was added and stirred at 50° C. for 12 hours. 10 ml of water was added thereto and the organic layer was batched off. The obtained aqueous layer was diluted with ethyl acetate and washed with 5 ml of 3 N hydrochloric acid and then with 5 ml of saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH2:19]Cl)=[C:12]([Cl:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1>[Ni].O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12]([Cl:21])[C:11]=3[CH:10]=[CH:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2ccc3c(Cl)c(CCl)cnc3c2=O)cc1
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2ccc3c(Cl)c(C)cnc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Raney Nickel 2800, slurry in H2O, active catalyst (2.5 g, 43 mmol) (wet weight) was rinsed off with ethanol and added to a suspension of 7-(4-methoxybenzyl)-4-chloro-3-(chloromethyl)-1,7-naphthyridin-8(7H)-one (1.00 g, 2.9 mmol) in 50 ml of EtOH. The reaction was stirred at RT for 30 min and then filtered off through a small pad of celite. The filtrate was concentrated under reduced pressure to give 7-(4-methoxybenzyl)-4-chloro-3-methyl-1,7-naphthyridin-8(7H)-one as a clear film. MS (M+H)+ 315.