Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH:15]=[C:14]1[C:23]([OH:25])=[O:24].[C:26](=[O:28])=[O:27]>CCCCCC.C1COCC1>[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]([C:26]([OH:28])=[O:27])=[C:14]1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: O=C(O)C1=COc2ccccc2O1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)C1=C(C(=O)O)Oc2ccccc2O1
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (185 ml, of a 1.42M solution in hexane) was added to a solution of diisopropylamine (37.0 ml), in dry THF (300 ml) at -78° and the the solution was stirred for 0.25 h. A solution of 1,4-benzodioxin-2-carboxylic acid (23.40 g) in dry THF (400 ml) was then added over 0.5 h and the resulting solution was stirred at -78° for 1 h. The solution was then poured onto finely crushed CO2 and the mixture left to stand overnight. The mixture was evaporated and 2N-hydrochloric acid (250 ml) was added cautiously, followed by concentrated hydrochloric acid (40 ml). EA (500 ml) and THF (100 ml) were added to the mixture, which was shaken and the organic layer separated. The aqueous phase was further extracted with EA and the combined extracts were dried. Evaporation of the solvent gave an orange solid which was triturated under ER for 0.5 h. The solid was collected, washed with ER and dried in vacuo to afford the title compound (25.0 g) m.p. 215°-218°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[Br:16]N1C(=O)CCC1=O.O.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Br:16])[C:11]([OH:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Br)c(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of 4-hydroxyisophthalic acid dimethyl ester (10.51 g) in THF (100 mL) was added N-bromosuccinimide (9.34 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (200 mL) and saturated aqueous sodium bicarbonate (100 mL) were successively added to the reaction solution. The resulting precipitate was filtered, washed successively with saturated aqueous sodium bicarbonate and water, and dried to give the title compound (12.5 g).
Reaction SMILES: CS([Cl:5])(=O)=O.ClC1C=CC(N[C:12]2[C:21]3[C:16](=[CH:17][C:18](OCCCNC)=[C:19](OC)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=C(F)C=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:5].[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[N:13][CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cl
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 185.6 %

Procedure:
Methanesulphonyl chloride (35 μl, 0.46 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylaminopropoxy)quinazoline (170 mg, 0.43 mmol) and triethylamine (67 μl, 0.48 mmol) in methylene chloride (3 ml). The mixture was stirred for 5 hours at ambient temperature the volatiles was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/acetonitrile/methanol (70/28/2). The purified product was dissolved in a mixture of methylene chloride/methanol (1/1) and 2M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation and the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6- methoxy-7-(E-methyl-N-methylsulphonyl]amino)propoxy)quinazoline hydrochloride (133 mg, 61%).
Reaction SMILES: O[N:2]1C(=O)C2=CC=CC=C2C1=O.[CH:13]1([CH2:21][OH:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([CH2:21][O:22][NH2:2])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCC1CCCCCCC1
Product: NOCC1CCCCCCC1

Procedure:
Prepared by a similar procedure as described for preparation 31. Starting materials: N-hydroxyphthalimide and cyclooctanemethanol (Acros). 13C-NMR (CDCl3) δ 82.3, 36.4, 29.4, 27.0, 26.5, 25.5.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:37][CH:36]([C:38]([OH:40])=[O:39])[CH2:35]1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:37][CH:36]([C:38]([OH:40])=[O:39])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CNC1
Product: O=C1N=C(N2CC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidine-3-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidine-3-carboxylic acid following General Procedure C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].CO.C1COCC1.[BH4-].[Na+]>[Cl-].[Na+].O>[OH:7][CH2:6][C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38 mmol) in 1:1 MeOH/THF (90 mL) was added NaBH4 (1.6 g, 42 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with brine, and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous layer was extracted with Et2O (3×100 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to provide 3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which was used in the next step without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:36])[C:5]2[N:10]=[C:9]([C:11]3[C:12]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[N:13][C:14]([CH2:17][N:18]4[N:22]=[N:21][C:20]([C:23]([F:26])([F:25])[F:24])=[N:19]4)=[N:15][CH:16]=3)[O:8][C:7](=[O:34])[C:6]=2[CH:35]=1.[CH3:37][NH2:38].C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:35]=[C:6]([C:7](=[O:34])[NH:38][CH3:37])[C:5]([NH:10][C:9]([C:11]2[C:12]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[N:13][C:14]([CH2:17][N:18]3[N:22]=[N:21][C:20]([C:23]([F:26])([F:24])[F:25])=[N:19]3)=[N:15][CH:16]=2)=[O:8])=[C:4]([CH3:36])[CH:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cnc(Cn4nnc(C(F)(F)F)n4)nc3-c3ccccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cnc(Cn2nnc(C(F)(F)F)n2)nc1-c1ccccc1Cl
Temperature: 45 °C
Reaction time: 0.25 h

Procedure:
100 mg (0.18 mmol) of 6-chloro-2-[4-(2-chlorophenyl)-2-{[5-(trifluoromethyl)-2H-tetrazol-2-yl]methyl}pyrimidin-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one were initially charged in 3 ml of THF, and 0.234 ml (0.46 mmol) of a 2 molar methylamine/THF solution was added at RT. The reaction mixture was then stirred at 45° C. for 15 min. After cooling, the mixture was concentrated and purified chromatographically on silice gel using cyclohexane/ethyl acetate. 48 mg (40% of theory; content 89%) of the desired product were isolated.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C:29]2[N:33]([CH3:34])[N:32]=[N:31][N:30]=2)[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][S:28][C:29]2[N:33]([CH3:34])[N:32]=[N:31][N:30]=2)[CH2:10]1
Reactant: Cn1nnnc1SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4nitrobenzyloxycarbonyl)pyrrolidine (1.67 g) in methanol (30 ml) was added conc. hydrochloric acid (0.82 ml) at ambient temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (80 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give (2S,4R)-4-hydroxy-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.25 g).
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3]([O:5]CC)=[O:4].[H-].[Na+].Cl[CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21].Cl>O1CCCC1.C(O)(=O)C.O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][CH2:2][C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
To a mixture of diethyl malonate (115.8 g) and tetrahydrofuran (300 mL) was added sodium hydride (60%, oil, 24.12 g) under ice-cooling. After stirring the mixture at room temperature for 30 min., a solution (100 mL) of 4-chloromethyl-5-methyl-2-phenyloxazole (50.0 g) in tetrahydrofuran was added to the reaction mixture under ice-cooling, and the mixture was heated under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was concentrated. Ethyl acetate was added to the residue and the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. A mixture of this oil, 6N hydrochloric acid (300 mL) and acetic acid (150 ml) was heated under reflux for 20 hrs. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (22.4 g, 40%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propionic acid from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-125° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[C:18]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)=[N:19][CH:20]=[CH:21][CH:22]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][C:17]3[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]4)=[N:19][CH:20]=[CH:21][CH:22]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncccc2N)C1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1C

Procedure:
Prepared analogously to example 1.1. from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (S)-tert-butyl 3-(3-aminopyridin-2-yloxy)piperidine-1-carboxylate (Intermediate X)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:19])([O-])[CH3:17].[K+].C(I)C(C)C>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:15][CH:16]([CH3:19])[CH3:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: CC(C)CI
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CC1CN(Cc2ccccc2)CCC1=O
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of potassium tert. butoxide (7.0 g, 59.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, isobutyl iodide (10.0 g, 54.0 mmole) was added at 10° C. The resulting mixture stirred for 16 hr at room temperature, refluxed for 3 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1-benzyl-3-isobutylpiperidin-4-one. Yield 1.0 g (9%), C16H23NO, m/z 246 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][F:30].O>CN(C)C=O.C(Cl)(Cl)Cl>[F:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][N:11]3[CH:18]=2)=[CH:4][C:3]=1[I:19]
Reactant: COc1ccc2nc(-c3ccc(O)c(I)c3)cn2c1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(OCCCF)c(I)c3)cn2c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 80.5 %

Procedure:
279 mg (corresponding to 0.763 mmol) of 2-(4′-hydroxy-3′-iodophenyl)-6-methoxyimidazo[1,2-a]pyridine that was dissolved in 10 mL of N,N-dimethylformamide, and 317 mg (corresponding to 2.29 mmol) of potassium carbonate was added thereto. The mixture was supplemented with 105 μL (corresponding to 1.15 mmol) of 1-bromo-3-fluoropropane, and then the solution was stirred at room temperature for 21 hours. After the completion of the reaction, the reaction solution was poured into water, and extracted three times with chloroform. The combined chloroform layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by recycle preparative HPLC (HPLC apparatus: LC-908 (under trade name; manufactured by Japan Analytical Industry Co., Ltd.); column: two JAIGEL 2H (under trade name; manufactured by Japan Analytical Industry Co., Ltd.) connected together; mobile phase: chloroform), to obtain 262 mg (corresponding to 0.614 mmol) of 2-[4′-(3″-fluoropropoxy)-3′-iodophenyl]-6-methoxyimidazo[1,2-a]pyridine (FIG. 1, Step 7).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([OH:12])[C:3]=1[Cl:13].[CH2:14]1CCN2C(=NCCC2)CC1.CI.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([O:12][CH3:14])[C:5]([O:10][CH3:11])=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COc1cc(C=O)c(Br)c(Cl)c1O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Product: COc1cc(C=O)c(Br)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Into 50 ml of acetonitrile were suspended 5.39 g (20.3 mmol), of 6-bromo-5-chlorovanillin, and 3.04 ml (20.3 mmol) of 1.8-diazabicyclo[5,4,0]-7-undecene and 2.53 ml (40.6 mmol) of methyl iodide were added dropwise under cooling with ice. After stirred for 5 hours at room temperature, 3.9 ml (22.33 mmol) if diisopropylethylamine and 2.53 ml (40.6 mmol) of methyl iodide were added under cooling with ice and the mixture was stirred for 20 hours at room temperature. After distilled off the solvent, 200 ml of dichloromethane were added to the residue, which was washed with water. After dried over anhydrous magnesium sulfate, the concentrated residue was purified by means of silica gel column chromatography (hexane-AcOEt 5:1) to obtain 4.04 g (yield 71%) of title compound as colorless needle-like crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N+:15]([O-])=O)[C:6]=1[OH:18])([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O.O>[NH2:15][C:7]1[C:6]([OH:18])=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 2,4-di-tert-butyl-6-nitro-phenol (27 mg, 0.11 mmol) and SnCl2.2H2O (121 mg, 0.54 mmol) in EtOH (1.0 mL) was heated in microwave oven at 100° C. for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO3 and filtered through Celite. The organic layer was separated and dried over Na2SO4. Solvent was removed by evaporation to provide 6-amino-2,4-di-tert-butyl-phenol (C-8), which was used without further purification. HPLC ret. time 2.74 min, 10-99% CH3CN, 5 min run; ESI-MS 222.5 m/z (MH+).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[OH:55][CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[O:64][CH3:65]>ClCCl.CO>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([O:64][CH3:65])=[C:58]([CH2:57][CH2:56][OH:55])[CH:63]=1
Reactant: COc1ccccc1CCO
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Br)cc1CCO
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
35.72 g of tetrabutylammonium tribromide are added in portions to a solution of 10.7 g of 2-(2-hydroxyethyl)-anisole in 195 ml of dichloromethane and 130 ml of methanol. The reaction mixture is stirred for 150 minutes at room temperature and is then concentrated by evaporation in a rotary evaporator. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane), yielding the title compound: Rf (dichloromethane)=0.26; HPLC Rt =13.04 minutes.
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[C:8]2[O:10][CH2:11][O:12][C:7]2=[CH:6][C:5]=1Br.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O.[CH3:26][O:27][C:28]([C:30]#[C:31][C:32]([O:34][CH3:35])=[O:33])=[O:29]>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]2[C:5]3[C:4](=[CH:9][C:8]4[O:10][CH2:11][O:12][C:7]=4[CH:6]=3)[C:3]([OH:14])=[C:30]([C:28]([O:27][CH3:26])=[O:29])[C:31]=2[C:32]([O:34][CH3:35])=[O:33])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(OC)c1cc2c(cc1Br)OCO2
Reactant: COc1cccc(C=O)c1
Product: COC(=O)c1c(C(=O)OC)c(-c2cccc(OC)c2)c2cc3c(cc2c1O)OCO3

Procedure:
2-Bromo-4,5-methylenedioxybenzaldehyde dimethyl-acetal, 3-methoxybenzaldehyde and dimethylacetylene-dicarboxylate are treated in the same manner as described in Example 1, whereby 1-(3-methoxyphenyl)-2,3-bis(methoxy-carbonyl)-4-hydroxy-6,7-methylenedioxynaphthalene is obtained.
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C([Cl:24])=O)CCCCC1.O.Cl.N1CCC(=O)CC1>>[Cl:24][C:4]1[CH:5]=[CH:6][C:1]([C:7]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[O:8])=[CH:2][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C1CCN(C(=O)C2CCCCC2)CC1
Agent: Cl
Agent: O=C1CCNCC1
Solvent: O
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1

Procedure:
N-cyclohexanecarbonyl-4-piperidone from cyclohexanecarbonyl chloride and 4-piperidone hydrochloride hydrate. Colourless crystals.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:15]1[C:19]2=[N:20][CH:21]=[C:22](C=O)[C:23]([O:24][N:25]=[C:26]([CH3:28])[CH3:27])=[C:18]2[CH:17]=[N:16]1)[CH3:14].Cl.C[CH2:33][O:34]CC>C1COCC1>[CH2:13]([N:15]1[C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH:33]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[OH:34])([O:24][N:25]=[C:26]([CH3:27])[CH3:28])[C:18]2=[CH:17][NH:16]1)[CH3:14]
Reactant: CCOCC
Reactant: CCn1ncc2c(ON=C(C)C)c(C=O)cnc21
Reactant: Brc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN1NC=C2C1=NC=CC2(ON=C(C)C)C(O)c1ccccn1
Reaction time: 0.5 h

Procedure:
Twenty-five ml of 1.44M n-BuLi was dissolved in 100 ml of anhydrous ether and chilled to -65°. 2-Bromopyridine (5.70 g) was then added dropwise and stirring was continued for 30 minutes. This solution was then added under nitrogen pressure through a catheter to 8.30 g of 1-ethyl-5-formyl-4-isopropylidenaminoxy-1H-pyrazolo[3,4-b]pyridine in 100 ml of THF at ice bath temperature. This reaction mixture was stirred for additional 30 minutes and then distributed between 5% hydrochloric acid and ether. The aqueous phase was washed well with ether and then made basic by pouring it over solid sodium bicarbonate. The product was extracted with dichloromethane and purified by preparative HPLC (5% methanol-dichloromethane, 200 ml/minute) to give 6.20 g of product, mp 131°-133° C. Recrystallization from dichloromethane-hexane raised the mp to 134°-135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]O.[CH3:14][C:15]1[CH:16]=[C:17]([C:22](=O)[CH3:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:23]=[CH:12][C:3]3[C:2](=[CH:7][CH:6]=[CH:5][C:4]=3[C:8]([F:11])([F:10])[F:9])[N:1]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: Nc1cccc(C(F)(F)F)c1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3c(C(F)(F)F)cccc3n2)c1
Temperature: 25 °C
Yield: 35.3 %

Procedure:
A mixture of (2-amino-6-(trifluoromethyl)phenyl)methanol (18 g, 94 mmol), 1-(3,5-dimethylphenyl)ethanone (19.5 ml, 130 mmol), powdered potassium hydroxide (0.90 g, 16.0 mmol), and RuCl2(PPh3)3 (0.45 g, 0.47 mmol) in toluene (310 ml) was refluxed overnight. Upon cooling to room temperature, the mixture was washed with water and extracted with ethyl acetate (3 times). The crude material was coated on celite and purified by CC starting with 5% EA in Heptanes. The product Obtained was recrystallized from methanol to afford 2-(3,5-dimethylphenyl)-5-(trifluoromethyl)quinoline (10 g, 35% yield) as yellow crystals.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][S:59]([N:62]1[CH2:67][CH2:66][CH:65]([NH2:68])[CH2:64][CH2:63]1)(=[O:61])=[O:60]>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:68][CH:65]5[CH2:66][CH2:67][N:62]([S:59]([CH3:58])(=[O:61])=[O:60])[CH2:63][CH2:64]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(S(C)(=O)=O)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-(methylsulfonyl)piperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.35 (m, 3H) 1.47-1.90 (m, 11H) 2.75-2.80 (m, 1H) 2.82 (s, 3H) 3.25 (s, 3H) 3.79-3.86 (m, 1H) 3.88 (s, 3H) 4.08 (t, 1H) 4.36-4.47 (m, 1H) 7.43 (dd, J=8.6, 1.77 Hz, 1H) 7.47 (d, J=1.8 Hz, 1H) 8.09 (d, J=8.3 Hz, 1H) 8.16 (s, 1H) 8.22 (d, 1H) 8.41 (br. s., 1H). [M+H] calc'd for C28H37F2N7O5S 622. found 622