Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=N[C@H](C1C=CC=CC=1)CC1C=CC(C)=CC=1)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(#N)C.C1CCCCC=1.[C:34](OOC(C)(C)C)(=[O:41])[C:35]1C=CC=CC=1>[Cu].C(O)(=O)C.C(OCC)(=O)C>[C:34]([O:4][CH:3]1[CH2:2][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:41])[CH3:35]
Reactant: Cc1ccc(C[C@H](N=Cc2ccccc2O)c2ccccc2)cc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu]
Solvent: C1=CCCCC1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1C=CCCC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 0.631 g of (S)-(-)-N-salicylidene-1-phenyl-2-(p-tolyl)ethylamine, 0.182 g of cupric acetate, 0.70 g of copper powder, 15 ml of acetonitrile, 10 ml of ethyl acetate, 5 ml of acetic acid, 15 ml of cyclohexene and 5 ml of t-butyl peroxybenzoate was stirred at 0° C for 24 hours in a nitrogen atmosphere. After removing the residual copper powder by filtration, the filtrate was admixed with 50 ml of benzene. The organic layer was successively washed with a 2N aqueous hydrochloric acid solution, water, an aqueous solution saturated with sodium hydrogen carbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was distilled under reduced pressure to obtain 1.90 g or 2-cyclohexenyl acetate. B.P. 75°-76° C/21 mmHg.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])[C:3]=1[N+:16]([O-])=O.O.O.Cl[Sn]Cl.[OH-].[Na+]>O1CCCC1.Cl>[NH2:16][C:3]1[C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(C(=O)c2ccc(Cl)cc2)c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C(=O)c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (5-methyl-4-nitroisoxazol-3-yl)-4-chlorophenylmethanone of Example Va (5.3 g, 20 mmoles) in tetrahydrofuran (THF) (100 ml) was added to a mixture of SnCl2.2H2O (27 g, 120 mmoles) in concentrated hydrochloric acid (35 ml) and THF (11 ml) over 1 hour. After warming to room temperature, the reaction mixture was poured into cold 10% sodium hydroxide (500 ml) with stirring and extracted with ethyl acetate. The extracts were washed with dilute sodium chloride and dried (sodium sulfate). Concentration gave 3.7 g (78%) of a solid, which was flash chromatographed (20% ethyl acetate:hexane) to yield 2.9 g (62%) of a solid, melting point 84°-86° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][NH2:12]>C(COC)OC>[Br:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][NH:12]2)=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=Cc1ccc(Br)cc1F
Solvent: COCCOC
Product: Brc1ccc2cn[nH]c2c1
Yield: 85.5 %

Procedure:
A solution of 2-fluoro-4-bromobenzaldehyde (5.09 g, 25 mmol) was dissolved in glyme (25 mL) and slowly treated over 10 minutes with anhydrous hydrazine (25 mL, 0.8 mol, 32 eq.). The resulting biphasic mixture was then held at reflux overnight. The reflux condenser was replaced with a short-path distillation head and about half the solvent distilled, at which time the reaction flask showed one phase and two phases were evident in the distillate. The undistilled residue was cooled and treated with water (25 mL), forming a white precipitate. This solid was collected by filtration, washed thoroughly with water, and dried in vacuo to give 6-bromoindazole (4.21 g, 85%) as white crystals.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[NH:23]1[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2B(O)O)=[N:26][N:25]=[N:24]1.C[O-].[Na+]>CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:19][CH2:18][CH2:17][CH2:16][C:15]([N:7]([C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[NH:23][N:24]=[N:25][N:26]=2)=[CH:22][CH:21]=1)=[O:20]
Reactant: OB(O)c1ccccc1-c1nnn[nH]1
Reactant: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Agent: [Pd]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: 70 °C
Yield: 58.1 %

Procedure:
A mixture made up of 1 g (2.70 mmol) of (4-bromobenzyl)-N-valeryl-L-valine, 0.513 g (2.70 mmol) of 2-(1H-tetrazol-5-yl)phenylboronic acid, 0.120 g of 5% Pd/C in paste (0.028 mmol of palladium) and 0.0084 g (0.032 mmol) of triphenylphosphine in a solution of 4.1 mL (21.5 mmol) of sodium methoxide in 30% methanol and 10 mL of methanol is heated at 70° C. for 10 h. The reaction is cooled to 20-25° C., the catalyst is filtered and the methanol distilled in vacuo. The resulting residue is dissolved in 25 mL of water and, following washing with 25 mL of AcOEt, is acidified to pH 3 with HCl 3N and extracted twice with 20 mL of AcOEt. The combined phases of AcOEt are dried with anhydrous Na2SO4 and following distillation of the solvent the crude product obtained is purified by silica gel chromatography (eluent AcOEt/heptane/AcOH 15:5:0.2) to provide 0.683 g (58%) of Valsartan.
Reaction SMILES: C([Li])(CC)C.CN(C)CCN(C)CCN(C)C.[C:18]([Si:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].CN([CH:38]=[O:39])C>O1CCCC1>[Si:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH:29]=1)[CH:38]=[O:39])([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
sec-Butyllithium (1.4M in cyclohexane, 2.78 ml) was added to dry tetrahydrofuran (10 mL) under nitrogen and the solution cooled to −78° C. N1-(2-(dimethylamino)ethyl)-N1,N2,N2-trimethylethane-1,2-diamine (0.674 g) was added slowly dropwise. A solution of tert-butyl(4-fluorophenethoxy)dimethylsilane (example 100, step a) (0.99 g) in dry tetrahydrofuran (3 mL) was then added dropwise over 5 minutes. Reaction mixture stirred for 2 hours at −78° C. DMF (2.1 ml) was added dropwise over 5 minutes and the mixture stirred at −78° C. for 1 hour followed by room temperature for 45 minutes. The reaction mixture was quenched by addition of water. Ethyl acetate (200 mL) was added and the organic washed three times with water, followed by twice with 2M HCl and then twice with water. The organic solution was washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 2% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.5 g.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Br:36]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O>[Br:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: CSc1nc(Br)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (77 mg) was dissolved in 5 ml of benzene at room temperature. N-bromosuccinimide (33 mg) and 5 mg of 2,2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 70 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-bromo-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:25][C:26]([N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+].O>C(COC)OC>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:36]5[CH:35]=[N:34][N:33]([C:26]([CH3:25])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=5)=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1

Procedure:
9-Bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411 (500 mg, 0.001 mol) and ethyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (594 mg, 0.0015 mol) were reacted under palladium catalyzed Suzuki coupling conditions with Pd(dppf)C12 and Cs2CO3 water and dimethoxyethane to give ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate together with the corresponding acid. LC/MS (ESI+): m/z 490 (M+H)
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][C:9]([CH3:11])=[N:8]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2nc(C)cc2C(=O)O)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2-(4-methoxyphenyl)-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.00 g, 3.84 mmol) in ethanol (20 mL) and water (20 mL) was added a sodium hydroxide solution (50% in water, 1 mL). The solution was stirred at 45° C. overnight. After the solution was allowed to cool to room temperature, 1 N HCl was added until the solution was acidic to pH paper. The solution was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4) and concentrated to give 761 mg of the title compound, which was used in the next reaction without further purification. LC-MS (C12H12N2O3 calculated 232) m/z 233 (M+H).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]4[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=4)[N:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CO>O>[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([O:32][CH3:33])[CH:25]=3)[N:20]=2)=[CH:11]1
Reactant: COc1cc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc(C(=O)O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1cc2nc(-c3c[nH]c4ccccc34)cc(C(=O)O)c2cc1OC

Procedure:
A stirred solution of (0.547 g) of 2-(N-phenylsulfonylindol-3-yl)-4-carboxy-6,7-dimethoxyquinoline, K2CO3 (0.380 g), MeOH (40 ml) and H2O (10 ml) are heated to reflux. The MeOH is evaporated in vacuo, and the aqueous residue diluted with more H2O, and acidified with 0.1N HCl to pH between 6-7 while contained in an ice-bath. An orange solid precipitates. This is collected, washed with ether then dried under vacuum (0.1 mm at 22° C.) for a few hours to obtain 2-(indol-3-yl)-4-carboxy-6,7-dimethoxyquinoline (m.p. 286° C. dec).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].C(OCC)(=O)C>CN(C)C=O>[N:1]1([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1F
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 1H-imidazole (0.61 g, 9.0 mmol) in dimethylformamide (8 ml) was added sodium hydride (60% in oil, 0.36 g, 9.0 mmol) and the reaction mixture was stirred at room temperature for 40 min. 2-Fluoro-benzonitrile (0.9 ml, 8.2 mmol) was added and the reaction was stirred at room temperature for 45 min, heated to 60° C. for 45 min and then stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water and brine. Drying and solvent evaporation gave 2-imidazol-1-yl-benzonitrile; 1H NMR (CDCl3, 400 MHz) δ7.86 (bs, 1H), 7.84 (m, 1H), 7.75 (m, 1H), 7.54 (m, 1H), 7.47 (dd, 1H, J=8.1 Hz, J=1 Hz), 7.36 (m, 1H), 7.27 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.[OH-].[Na+:33]>O.C(O)(C)(C)C>[Na+:33].[Na+:33].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1

Procedure:
2.5 grams of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (purity 99.6% HPLC) were dissolved in a mixture of 0.3 L of distilled water and 0.2 L of t-butanol with the addition of 5.849 mL of a 2.0M standard solution of sodium hydroxide in water. The pH of the solution was adjusted to 7.14 by adding a diluted solution of sodium hydroxide in water and a suspension of N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid in the same solvent. The obtained solution was dried in a freeze-drier affording the title compound as a white solid (2.7 g, purity 99.6% area by HPLC). Acidimetric titrations of the final product can be used to confirm the absence of residual sodium hydroxide and pemetrexed diacid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]([F:17])([F:16])[F:15].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>O1CCCC1>[F:15][C:14]([F:17])([F:16])[O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[B:18]([OH:23])[OH:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1OC(F)(F)F
Reaction time: 0.75 h
Yield: 65.1 %

Procedure:
n-Butyllithium (5.9 ml, 9.5 mmol) was added to a solution of 1-bromo-2-(trifluoromethoxy)benzene (2 g, 8.2 mmol) in tetrahydrofuran (28 ml) at −78° C. and stirred for 45 minutes. Triisopropyl borate (2.58 ml, 11.1 mmol) was added dropwise to the reaction mixture and the solution was slowly brought to room temperature over 16 hours. The reaction mixture was quenched with water, made basic with 2N NaOH and extracted with ethyl acetate. The aqueous solution was acidified with 2N HCl, stirred for 1 hour at room temperature and extracted into ethyl acetate. The organic layer was washed with water, brine solution and dried over sodium sulfate. It was filtered and concentrated to give the product (1.10 g, 65%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl>O1CCOCC1.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]>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][CH:7]=1
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Brc1cnc(-c2ccccc2)nc1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
A mixture of 5-bromo-2-iodopyrimidine (285 mg, 1.0 mmol), potassium phosphate (637 mg, 3.0 mmol), phenylboronic acid (134 mg, 1.1 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (73 mg, 0.1 mmol) in dioxane (5 mL) was heated to 120° C. for 20 minutes in a microwave. LC/MS analysis of the reaction indicated that the reaction was complete. DCM (10 mL) was added, and the precipitates removed by passing through a plug of celite. The filtrate was concentrated, and the crude residue purified by flash column chromatography, gradient elution (0 to 100%) hexane/ethyl acetate, to afford compound Int-1a as a white solid (201 mg, 86% yield). HPLC-MS tR=1.39 min (UV254 nm); mass calculated for formula C10H7BrN4 233.98, observed LCMS m/z 235.0 (M+H).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>CC(O)C>[CH2:29]([NH:32][CH2:28][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:27])[C:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12]2)=[CH:7][CH:6]=1)[CH:30]=[CH2:31]
Reactant: C=CCN
Reactant: O=c1c(-c2ccccc2)c(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Solvent: CC(C)O
Product: C=CCNCC(O)COc1ccc2c(=O)c(-c3ccccc3)c(-c3ccccc3)oc2c1

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)-2,3-diphenychromone and allylamine afforded the desired amine as white needles, m.p. 119°-120° (iPrOH); yield, 82%. Its hydrochloride salt had m.p. 140°-142° (iPrOH/phCH3); containing water).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:21][F:22])([CH2:19][F:20])[CH:7]=1)=[O:5])[CH3:2].[Cl-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:21][F:22])([CH2:19][F:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Yield: 13.7 %

Procedure:
A mixture of 42.0 g of 2,2-bisfluoromethyl-6-nitro-2H-1-benzopyran-4-carboxylic acid ethyl ester, 88 g of stannous chloride and 500 ml of ethyl alcohol was heated to reflux for 2 hours. The reaction mixture was combined with an aqueous 2N sodium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried over sodium sulfate and concentrated under reduced pressure to give 5.2 g of 6-amino-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[NH2:14][C:15]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:14][C:15]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:10])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(OCC)cc2)CC1
Yield: 84 %

Procedure:
Combine 4-ethoxybenzoic acid (10.0 g, 60.18 mmol), ethyl 1-aminocyclopropanecarboxylate hydrochloride (commercially available, 10.96 g, 66.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (13.84 g, 72.21 mmol), and 1-hydroxybenzotriazole (HOBT) (9.76 g, 72.21 mmol) in tetrahydrofuran (500 mL). Add diisopropylethylamine (DIEA) (23.09 mL, 132.39 mmol) over 3-5 minutes and stir the reaction for approximately 16 hours at ambient temperature under nitrogen. Dilute the mixture with ethyl acetate, wash with dilute HCl, dilute NaHCO3, and then brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure. Purify the residue by recrystallization from ethanol to give the title compound (13.93 g, 84%) as a white solid: MS (m/z): 278 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15]>CN(C)C=O.O>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15])=[N+:2]=[N-:3]
Reactant: COc1c(Br)ccnc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N=[N+]=[N-])ccnc1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.2 %

Procedure:
To 1 g (0.0155 moles) of sodium azide in 25 ml of dimethylformamide at 0° C., there is added gently 3 g (0.0141 moles) of 4-bromo-2-cyano-3-methoxypyridine from Example b), dissolved in 40 ml of dimethylformamide. The mixture is stirred for 6 hours at ambient temperature. The reaction mixture is diluted in 200 ml of iced water and extracted with dichloromethane. The organic phase is washed twice with water, dried, concentrated and the residue chromatographed (ethyl acetate/heptane, 3:7). There is obtained 0.87 g (35% yield) of a white solid (MP=102° C.).
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl.C(OCC)C>[Cl:23][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:10][CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(F)cccc1CO
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(F)cccc1CCl
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of (3-fluoro-2-methoxyphenyl)methanol (3.02 g, 19.3 mmol) and triethylamine (6.74 mL, 48.4 mmol) in dichloromethane (20 mL) is treated with methanesulfonyl chloride (2.99 mL, 38.7 mmol) slowly at room temperature and stirred under nitrogen for 3 h. The reaction is the diluted with diethyl ether, washed with 0.5 M hydrochloric acid twice, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as a yellow oil (2.71 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.15-6.93 (m, 3H), 4.61 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=O)[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[OH-].[Na+]>C(O)CCC>[NH2:2][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1=[O:11]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: NC1CCCCNC1=O
Temperature: 117 °C

Procedure:
30 mmols of L-lysine hydrochloride 1 is neutralized with 30 mmols of NaOH and then 270 mmols of Al2O3 is added, followed by the addition of 120 ml of 1-butanol. This mixture is heated to 117° C. and is refluxed for six hours. The yield of α-amino-ε-caprolactam 2 produced by this reaction is about 92%.