Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].ClCl.N1C(=O)CC(=O)NC1=O>C(Cl)Cl.CO>[C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: ClCl
Agent: O=C1CC(=O)NC(=O)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)NCCN(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.61 g (0.01 mole) sample of (±)-N-[2-(acetylmercaptomethyl)-4-methyl-1-oxopentyl]glycine is slurried in 50 ml of CH2Cl2. Triethylamine (1.08 g, 0.01 mole) is added to give a solution which is cooled to -10° C. and treated with 1.08 g (0.01 mole) of ethyl chloroformate. After 1/2 hour, a solution of N,N-dimethylethylenediamine (0.88 g, 0.01 mole) in 10 ml of CH2 Cl2 is added, and stirring from -5° C. to +25° C. continued for 2 hours. The mixture is evaporated and triturated with ethyl acetate. The triethylamine hydrochloride is filtered and the filtrates evaporated to an oil, 3.6 g. A 2.95 g sample of oil is dissolved with 1 equivalent of barbituric acid in methanol, filtered and evaporated to a foam. Addition of acetonitrile gives a white solid which is washed (briefly) with absolute ethanol and then acetonitrile. Recrystallization from 100 ml of acetonitrile gives a white powder, 1.3 g of (±)-N2 -[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]-N-[2-(dimethylamino)ethyl]glycinamide, barbituric acid (1:1) salt (34%), m.p. 151°-154°, which analyzes correctly for a salt with 1.0 mole of barbituric acid and 0.5 mole of water.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[C:14]2[N:16]([C:20]3[C:32]([Cl:33])=[CH:31][C:23]([O:24][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[C:22]([O:34][CH2:35][C:36]4[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=4[F:44])[CH:21]=3)[C:17](=[O:19])[NH:18][C:13]2=[C:12]([CH3:45])[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[Cl:33][C:32]1[C:20]([N:16]2[C:14]3=[N:15][C:10]([CH2:9][OH:8])=[CH:11][C:12]([CH3:45])=[C:13]3[NH:18][C:17]2=[O:19])=[CH:21][C:22]([O:34][CH2:35][C:36]2[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:37]=2[F:44])=[C:23]([CH:31]=1)[O:24][CH2:25][C:26]([N:28]([CH3:29])[CH3:30])=[O:27]
Reactant: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(C)cc(CO[Si](C)(C)C(C)(C)C)nc32)c(Cl)cc1OCC(=O)N(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(F)c1COc1cc(-n2c(=O)[nH]c3c(C)cc(CO)nc32)c(Cl)cc1OCC(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.4 %

Procedure:
To a solution of 2-{4-[5-(tert-butyldimethylsilyloxy)methyl-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one-3-yl]-5-chloro-2-(2-fluoro-6-methoxybenzyloxy)phenoxy}-N,N-dimethylacetamide (40 mg) in tetrahydrofuran (0.6 mL) was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 1.2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate=2/1), and collected by filtration. The collected solids were dried under reduced pressure to give the title compound (16 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:49][CH2:50][C:51]2[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=2[CH3:57])=[O:14])=[CH:15][CH:16]=1)[CH3:7]
Reactant: CC(Oc1cccc(Br)c1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccc(Br)c3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of 4-(1-(3-bromophenoxy)ethyl)benzoic acid (0.9 g, 2.8 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4.0 mmol) and 1-hydroxybenzotriazole (0.54 g, 4.0 mmol) in dichloromethane (20 mL) was added triethylamine (0.8 g, 8.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.76 g, 5 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel: dichloromethane: methanol=20:1) to give pure product 4-(1-(3-bromophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (1.2 g, 93%) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:35].[K+]>O>[C:9]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C=O)s1
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)O)s1

Procedure:
25 g of N-(5-formyl-thien-2-yl)-N-hexadecylacetamide are dissolved in 20 cc. of pyridine. A solution of 6.7 g of potassium permanganate in 90 cc. of pyridine and 40 cc. of water is added with stirring and cooling such that the temperature of the reaction mixture does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvents are distilled off, the residue is triturated with dilute hydrochloric acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>C(#N)C>[OH:5][P:1]([O:4][P:1]([OH:4])([OH:3])=[O:2])(=[O:3])[OH:2].[CH3:6][O:7][C:8]1[N:13]=[C:12](/[CH:14]=[CH:15]/[C:16]2[N:34]=[C:19]3[C@H:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][CH2:23][N:18]3[N:17]=2)[CH:11]=[CH:10][C:9]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1
Reactant: O=P(O)(O)O
Agent: COc1nc(/C=C/c2nc3n(n2)CCC[C@H]3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Solvent: CC#N
Product: O=P(O)(O)OP(=O)(O)O

Procedure:
A solution of phosphoric acid (52.8 mg) in acetonitrile (0.2 mL) was added to a solution of (8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (100 mg) in acetonitrile (0.8 mL) at room temperature. The precipitated oil was solidified as a result of stirring with spatula. The solid was collected by filtration through a glass filter. The solid was washed with ice-cold acetonitrile, air-dried at room temperature for 10 minutes and then dried under reduced pressure at room temperature to obtain 120 mg of the title compound as white solid crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2O)=[O:14])=[CH:4][C:3]=1[C:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:6][C:5]([CH2:12][C:13]2[O:14][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:4][C:3]=1[C:23]([CH3:25])([CH3:24])[CH3:26]
Reactant: CC(C)(C)c1cc(CC(=O)Nc2ccccc2O)cc(C(C)(C)C)c1O
Solvent: CCCCCC
Product: CC(C)(C)c1cc(Cc2nc3ccccc3o2)cc(C(C)(C)C)c1O

Procedure:
A sample of N-[4-hydroxy-3,5-di-t-butyl-phenyl-acetyl]-2-hydroxyaniline (12.0 g, 0.033 mol) was heated at 260° under nitrogen for 50 minutes. After cooling, the material was heated at reflux with hexane (50 ml) until most of the sample was dissolved. The mixture was filtered while hot and allowed to cool. Filtration afforded 5.4 g (49%) of nearly pure title compound. Pure title compound was obtained after two further crystallizations (with charcoal) from hexane, mp 94-96° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([NH2:20])[C:12]=1[C:13]#[N:14]>O1CCOCC1>[NH2:20][C:15]1[C:12]([C:13]#[N:14])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:18]=[C:17]([NH2:19])[CH:16]=1
Reactant: N#Cc1c(N)cc(N)nc1Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1c(N)cc(N)nc1Oc1ccccc1
Temperature: 190 °C
Reaction time: 0.25 h

Procedure:
A heavy walled, sealable tube suitable for microwave heating was charged with 60 mg (1.5 mmol) of NaH (60% dispersion in mineral oil) and 3 mL of dioxane. To the suspension was added 150 mg (1.59 mmol) of phenol, then the mixture was stirred for 15 min. Next, 212 mg (1.00 mmol) of 2-bromo-4,6-diaminonicotinonitrile was added. The tube was sealed, and the mixture was heated with a microwave apparatus at 190° C. for 25 minutes then cooled and concentrated under reduced pressure. The residue was diluted with 10 mL of toluene and concentrated again under reduced pressure. The remaining material was taken up in 20 mL of ethyl acetate and extracted with 2M NaOH(aq.) (3×5 mL), and brine (1×5 mL), draining some red precipitate with the aqueous layers. The organic layer was dried over MgSO4, filtered, and concentrated to 178 mg (79%) of an orange solid. The product could be further purified via silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes to provide a white solid. 1H NMR (300 MHz, d6-DMSO) δ 7.38 (m, 2H), 7.17 (m, 1H), 7.10 (m, 2H), 6.37 (s, 2H), 6.25 (s, 2H), 5.41 (s, 1H); MS (ESI) m/e=227 (M+H)+, 225 (M−H)−.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Se](=O)=[O:19].[OH2:21]>O1CCOCC1>[OH2:8].[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:19])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH:16]=[O:21])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(OCC2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(OCC2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 18.5 h

Procedure:
A mixture of 12.0 g of 4'-(cyclohexylmethoxy)acetophenone, 5.8 g of selenium dioxide, 1.4 ml of water and 70 ml of p-dioxane was refluxed with stirring at 120° C. for 18.5 hours, cooled and filtered through diatomaceous earth, washing with p-dioxane. The combined filtrate and wash was poured into 200 ml of water cooled to 8° C. The yellow solid was collected and dried. An 8.1 g portion of sodium bisulfite was dissolved in 500 ml of water. To this was added a solution of the above solid in a mixture of 300 ml of ethanol and 100 ml of p-dioxane. The resulting mixture was filtered and the filtrate stored at 0° C. for 48 hours. The resulting solid was collected, washed twice with water, p-dioxane and absolute ethanol and then dried. This solid was added to 535 ml of 0.5N hydrochloric acid and heated with stirring at 75° C. for 8 minutes and then cooled to 10° C. The solid was collected, dissolved in hot p-dioxane, filtered and 20 ml of water added to the filtrate. The filtrate was cooled to 0° C., giving the desired product as a white solid, m.p. 118°-121° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.[CH3:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=[C:26]([NH2:39])[N:25]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].COCCOC>[NH2:39][C:26]1[N:25]=[C:24]([CH3:23])[C:29]([C:2]2[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([S:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=3)(=[O:10])=[O:9])[CH:7]=2)=[CH:28][N:27]=1
Reactant: O=S(=O)(Nc1ccc(C(F)(F)F)cn1)c1cc(Br)ccc1Cl
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(N)ncc1-c1ccc(Cl)c(S(=O)(=O)Nc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C

Procedure:
A 5 ml microwave tube is charged with 5-bromo-2-chloro-N-(5-trifluoromethyl-pyridin-2-yl)-benzenesulfonamide (0.067 g, 0.16 mmol) and DME (degassed 3 ml), 4-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-pyrimidin-2-ylamine (Intermediate G) (0.0535 g, 0.19 mmol), 2 M aqueous Na2CO3 solution (640 μl) and PdCl2(dppf).DCM (0.00448 g, 5.4 μmol) and the mixture is heated using microwave radiation at 110° C. for 15 min. After cooling to room temperature the mixture is taken up in ethyl acetate (50 ml), washed with water, dried over MgSO4 and concentrated in vacuo. The crude product is triturated with DCM (0.5 ml), filtrated and washed with DCM to afford the pure title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([Cl:20])[CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:29])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:18]([Cl:20])[CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1cnc(NC(=O)OC(C)(C)C)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A solution of KOH (0.44 g, 6.72 mmol, 85%) in ethanol (5 ml) was added to a solution of 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.45 g, 6.11 mmol) in ethanol (25 ml) and methylene chloride (10 ml) at 0° C. The mixture was stirred for 18 h at room temperature. The solvent was evaporated in vacuo and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1 M HCl and extracted with methylene chloride and ethyl acetate. The combined organic layers were washed with water and brine and dried. Filtration and concentration under reduced pressure gave the crude product which was purified by flash chromatography (10% MeOH in CH2Cl2) giving 2-(6-tert-butoxycarbonylamino-5-chloro-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.41 g, 62%) as a yellow-white glassy foam.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:16].C(OC([N:24]1[CH2:28][C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][C@H:25]1[C:37](O)=[O:38])=O)(C)(C)C>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:37]([C@@H:25]3[CH2:26][C@@H:27]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][NH:24]3)=[O:38])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(Oc2ccc(N)cc2)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(F)cc2)C[C@H]1C(=O)O
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3)cc2)ccc1F
Yield: 73 %

Procedure:
Proceeding as in Reference 6, but substituting 4-(4-fluoro-3-methylphenoxy)aniline and (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid, gave (2S,4R)—N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (282 mg, 73%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:9]([C:15]([OH:14])=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:22]=[N:8]2)=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1O
Temperature: 25 °C

Procedure:
A mixture of 3-t-butylaniline (67.6 g.) and diethyl ethoxymethylenemalonate was heated on the steam bath for 3 hours, the ethanol formed being collected by distillation. The resulting yellow oil was dissolved in diphenyl ether (200 ml.) and added during 0.5 hour to stirred diphenyl ether (800 ml.) at 250°-260°, the ethanol formed being collected by distillation. The mixture was stirred at 250°-260° for 0.5 hour, then allowed to cool to room temperature and diluted with an equal volume of petroleum ether (b.p. 60°-80°). The precipitate was collected by filtration to give the novel compound ethyl 7-t-butyl-4-hydroxyquinoline-3-carboxylate, m.p. 279°-281°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:15]Br>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[C:10]([Br:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(C)oc12
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc2c(Br)c(C)oc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 2-methyl-benzofuran-7-carboxylic acid methyl ester (0.55 g, 2.87 mmol), prepared according to a literature procedure (Ishikawa, T.; Nagai, K.; Ohkubo, N.; Ishii, H. Heterocycles 1994, 39, 371), in CH2Cl2 (15 mL) at 0° C. is treated with bromine (147 μL, 2.87 mmol). The reaction is stirred at 0° C. for 30 min, then at RT overnight. The reaction is diluted with EtOAc 960 mL); washed with 5% Na2S2O3 (2×20 mL); brine (20 mL); dried with Na2SO4, filtered and concentrated gives the title compound (0.79 g, 2.87 mmol, 100%). 1H NMR (CDCl3): δ 2.55 (s, 3H), 4.00 (s, 3H), 7.33 (t, J=7.5 Hz, 1H), 7.63 (dd, J=7.9, 0.9 Hz, 1H), 7.93 (dd, J=7.9, 0.9 Hz, 1H) ppm.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([OH:12])=O.[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][CH:20]=[C:19]2[C:23]1[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=1>>[Cl:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][CH:20]=[C:19]2[C:23]1[CH2:24][CH2:25][N:26]([C:10]([CH:2]2[CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)=[O:12])[CH2:27][CH:28]=1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: O=C(O)C1Cc2ccccc2C1
Product: O=C(C1Cc2ccccc2C1)N1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
Prepared from 9a and 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2O.P(Br)(Br)([Br:21])=O.[OH-].[NH4+]>CN(C=O)C>[Br:21][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=[N:9][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1c(-c2ccccc2)nnc2c(Cl)cccc12
Reactant: O=P(Br)(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cccc2c(Br)c(-c3ccccc3)nnc12
Temperature: 0 °C
Yield: 12.5 %

Procedure:
A solution of 8-chloro-3-phenylcinnolin-4-ol (2.40 g, 9.3 mol) and POBr3 (10.0 g, 35 mmol) in DMF (100 mL) was heated to 50° C. for 2 hours. The reaction was poured into ice-water, adjusted to pH to ˜10 by diluted ammonium hydroxide and extracted with ethyl acetate. The combined organics were concentrated to yield 4-bromo-8-chloro-3-phenyl-cinnoline (1.40 g) as a pale yellow solid. MS m/z 321, 323 [M+H]+;
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].NC1C=CC(O)=CC=1F>>[NH2:9][C:5]1[CH:4]=[C:3]([OH:12])[CH:2]=[CH:7][C:6]=1[F:8]
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Agent: Nc1ccc(O)cc1F
Product: Nc1cc(O)ccc1F

Procedure:
This compound was prepared from 2-bromo-4-fluoro-5-nitrophenol (3.1 g, 13.1 mmol) in the manner described for 4-amino-3-fluorophenol, affording quantitative yield of crude 3-amino-4-fluorophenol which was used without further purification. 1H-NMR (DMSO-d6) δ 8.60 (br s, 2H), 7.12 (dd, J=7.8, 6.6 Hz, 1H), 6.82 (dd, J=5.1, 1.5 Hz, 1H), 6.55 to 6.61 (m, 1H).
Reaction SMILES: [BH4-].[Li+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15]3=[N:16][C:17]4[C:18](=[C:19]([C:24](OC)=[O:25])[CH:20]=[CH:21][C:22]=4[Cl:23])[N:14]3[CH2:13][CH2:12][CH2:11]2)=[C:6]([CH3:28])[CH:5]=1>O1CCCC1>[Cl:23][C:22]1[C:17]2[N:16]=[C:15]3[N:10]([C:7]4[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=4[CH3:28])[CH2:11][CH2:12][CH2:13][N:14]3[C:18]=2[C:19]([CH2:24][OH:25])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 50 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Under nitrogen atmosphere, lithium borohydride (1.00 g, 46.0 mmol) was added to a suspension of methyl 1-(4-bromo-2-methylphenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (5.0 g, 11.5 mmol) in tetrahydrofuran (70 mL) at 0° C., and the mixture was stirred at 50° C. for 20 h. The reaction mixture was quenched by aqueous saturated ammonium chloride at 0° C., and the mixture extracted with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product of the title compound as a white powder (4.68 g, 11.5 mmol, quant.).
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])[C:5](=[O:8])[CH2:6][NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccccc1N(C(=O)CBr)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1N(C(=O)CNc1ccccc1Nc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of N-Isopropyl-N-(2-methoxy-phenyl) bromoacetamide, prepared as in Part B, (10.0 g 34.9 mmol), N-phenyl phenylenediamine (6.41 g, 34.9 mmol) and potassium carbonate (4.82 g) in DMF (100 mL) is stirred at RT for 48 h. The reaction mixture is filtered through celite and the filtrate concentrated in vacuo. Purification by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent gave N-Isopropyl-N-(2-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamideas a light brown foam (4.50 g): 1H NMR (300 MHz, CDCl3) δ7.46 (t, 1H, J=7.9), 7.030-7.05 (m, 8H), 6.98 (t, 1H, J=6.8), 6.84 (m, 2H), 6.70 (t, 1H, J=7.6), 6.37 (d, 1H, J=8.0), 5.4 (s, br, 1H), 4.95 (m, 1H, J=6.8), 3.84 (s, 3H), 3.45 (dd, 2H, J=23.2, 6.6), 1.20 (d, 3H, J=6.8), 1.01 (d, 3H, J=6.8).