Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:15]=[CH:14][C:10]=1[C:11]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.3 %

Procedure:
A solution of 2,4-dibenzyloxybenzoic acid (3.34 g) and methyl glycinate hydrochloride (1.25 g) in DMF (40 mL) is treated with triethylamine (2.23 g) and 1-hydroxybenzotriazole (1.53 g) at 0° C. The mixture is stirred for 10 minutes, treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride (2.05 g) and allowed to warm to 25° C. The solution is evaporated. The residue is partitioned between ethyl acetate and water. The organic layer is washed with 1 M HCl, 1 M NaOH, water, dried and evaporated. The residue is recrystallized from methanol to yield methyl N-(2,4-dibenzyloxybenzoyl)glycinate as a solid (900 mg). H NMR (CDCl3) 3.7(3H,s), 4.2(2H,d), 5.1 (2H,s), 5.2(2H,s), 6.6(1H,s), 6.7(1H,d), 7.3-7.5(10H,m), 8.2(1H,d), 8.4(1H,t).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncnn2cc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 80 °C

Procedure:
A suspension of ethyl 4-amino-5-(4-nitrophenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (1.04 g, 3.18 mmol) in ethanol (10 mL), THF (5 mL) and 1N aqueous sodium hydroxide solution (5.56 mL, 5.56 mmol) was heated (80° C.) for 6 h. The homogeneous solution was cooled to rt and treated dropwise with 1N hydrochoric acid (5.56 mL). The reaction was concentrated in vacuo and the resulting solid triturated with water to give the desired product in quantitative yield. This material could be used without further purification. ES-MS 300.2 (MH)+; HPLC RT (Method A) 1.37 min.
Reaction SMILES: C([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)CC1COc1ccccc1CCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](O)CC1COc1ccccc1CCc1ccccc1
Yield: 97.5 %

Procedure:
A solution of 390 mg of (4R)-4-benzyloxy-1-t-butoxycarbonyl-2-[2-(2-phenylethyl)phenoxymethyl]pyrrolidine [prepared as described in step (a) above] in 25 ml of ethanol was stirred at 60° C. for 5 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 100 mg of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 310 mg (yield 97%) of the title compound as a colorless oil.
Reaction SMILES: [Mg].[C:2]1([Si:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(Cl)Cl)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[CH:18][CH:19]=[CH2:20].[Cl-].[NH4+]>CCOCC.C(O)CO.C1COCC1>[C:2]1([Si:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:20][CH:19]=[CH:18][CH2:17]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=C
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: OCCO
Product: C1=CC[Si](c2ccccc2)(c2ccccc2)C1
Temperature: -20 °C
Yield: 64 %

Procedure:
Into a 1000 mL three necked rb flask, equipped with a reflux condenser was placed magnesium powder (26.4 g)(1.1 mol), diphenyldichlorosilane (253 g)(1 mol) and THF (500 mL). The reflux condenser was connected to a refrigeration unit with ethylene glycol cooled at -20° C. circulating. With stirring, 1,3-butadiene (81 g) (1.5 mol, 125 mL) at -78° C. Was transferred to this reaction system via a cannula. The reaction mixture was stirred over 72h. The reaction mixture was hydrolyzed with saturated ammonium chloride solution (100 mL) and 100 ml ether was added. The organic solution was separated. The water layer was washed with ether (2×50 mL). The combined organic solution was dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The product was purified by distillation through a 10 cm vacuum jacketed Vigreux column. A fraction, bp 155°-7° C./0.2 mmHg, 154 g, 64% yield was collected. The following spectra properties were observed. 1H NMR (δ)1.97 (d,4H, J=0.94Hz), 6.15(t,2H,J=0.94Hz), 7.44-7.53 (m,6H), 7.67-7.71 (m,4H). 13C NMR (δ) 16.84, 127.90, 129.45, 131.00, 134.67, 135.71, 29Si NMR (δ) 8.51.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:32])(=[O:31])[CH:28]([CH3:30])[OH:29].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:32][C:27](=[O:31])[CH:28]([CH3:30])[OH:29])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC(O)C(=O)[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 30 ml of DMF is dissolved 3.4 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one, and 2.5 ml of 70% aqueous sodium lactate is added. The mixture is stirred at room temperature (15°-25° C.) for 3 hours and poured into a mixture of 350 ml of ethyl acetate and 30 ml of water. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 100 ml of dichloromethane and 700 ml of diisopropyl ether in that order, elution is carried out with 1200 ml of diisopropyl ether-ethyl acetate (10:1). The eluate is evaporated under reduced pressure to remove the solvent, giving 3.0 g of the above-identified compound as a light yellow oil.
Reaction SMILES: [H][H].[C:3](#[N:12])[C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=1>[Ni]>[C:7]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=1)[CH2:3][NH2:12])#[N:8]
Reactant: N#Cc1cccc(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Product: N#Cc1cccc(CN)c1

Procedure:
600 g of m-cyanobenzylamine crude product (m-cyanobenzylamine 90% by weight, m-xylylenediamine 10% by weight) obtained by hydrogen reduction of isophthalonitrile in the presence of sponge metal nickel catalyst was added dropwise in 8 kg of water while stirring at room temperature for dissolution and the solution was left to stand overnight at 5C. The crystals which precipitated were filtered by centrifugation to obtain 783 g of m-cyanobenzylamine hydrate (water content: 48% by weight).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Clc1nccc(-c2cccs2)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4cccs4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for C27H24N4OS, 452.57; m/z found, 453.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-2-ethyl-benzoic acid (115 mmol) in anhydrous THF (380 mL) at 0° C. was added BH3.THF complex (1.0 N solution in THF, 230 mL) over 30 min. The resulting mixture was slowly warmed up to room temperature and the stirred for 15 hours. The reaction was carefully quenched with slow addition of water. The solvent was removed and the residue was taken up in EtOAc. The organic layer was washed with 1.0 N HCl, H2O, brine and dried over MgSO4. The solvent was removed to afford the desired product. (22 g, 89% yield). 1H NMR (300 MHz, CDCl3): δ 1.23 (t, J=7.5 Hz, 3 H), 2.64-3.01 (m, 2H), 4.68 (s, 2H), 7.24-7.26 (m, 1H), 7.32-7.36 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.C1(C)C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CCOCC.O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:26][NH:27][CH:28]=2)=[CH:15][CH:16]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c[nH]cc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 25.6 %

Procedure:
To a mixture of 5.63 g of a 60% sodium hydride/oil suspension in 200 mL of dry ether under nitrogen is added from an additional funnel a mixture of 23.5 g (122 mmol) of ethyl p-chlorocinnamate and 9.4 g (122 mmol) of (p-tolylsulfonyl)methyl isocyanide in solution in 180 mL of ether and 80 mL of dimethylsulfonide. The addition time is about 20 minutes and results in gentle refluxing of the mixture. After another 10 minutes stirring, the mixture is diluted with 100 mL of water. The mixture is extracted four times with ether which is then dried over magnessium sulfate followed by concentrated in vacuo. The resulting solid is recrystallized from ethylene dichlorite to give 7.8 g of crystals, m.p. 137°-138° C.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[C:13](OC(C)=C)(=[O:15])[CH3:14]>O1CCCC1>[C:13]([O:12][CH2:11][C@H:9]([OH:10])[C@H:7]1[O:8][C:2](=[O:1])[C:3]([OH:4])=[C:5]1[OH:6])(=[O:15])[CH3:14]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: C=C(C)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
Reaction time: 22 h
Yield: 90.8 %

Procedure:
Four grams of the immobilized Lipase PS prepared by the same procedure as in Example 2 was added to 40 ml of a dry tetrahydrofuran solution containing 4 g of ascorbic acid and 3 g of isopropenyl acetate, and then the reaction was continued for 22 hours at 40° C. The reaction mixture was then filtered, concentrated and recrystallized from acetone-benzene to yield 4.5 g of ascorbic acid-6-acetate. The water content of the reaction system was 700 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:20]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:7]1=[O:11])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(C2(Cc3ccccc3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 4b supra), benzyl bromide (0.12 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 23 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40S, dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product. Attempts to recrystallize the product failed. Sample was concentrated to give rac-3-benzyl-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a colorless glass. (Yield 0.17 g, 77.9%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:15]([F:18])([F:17])[F:16])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[Br:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28]Br)=[CH:22][CH:21]=1>C1COCC1>[Br:19][C:20]1[CH:34]=[CH:33][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][O:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH3:4])=[CH:11][CH:10]=2)[C:15]([F:16])([F:17])[F:18])=[CH:22][CH:21]=1
Reactant: BrCc1cccc(Oc2ccc(Br)cc2)c1
Reactant: CCOc1ccc(C(CO)C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(C(COCc2cccc(Oc3ccc(Br)cc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 30.8 %

Procedure:
Under a nitrogen atmosphere, 171 mg of sodium hydride (60% oil dispersion) was added to 20 ml of dry THF. A solution of 1.0 g of 2-(4-ethoxyphenyl)-3,3,3-trifluoropropanol and 1.30 g of 3-(4-bromophenoxy)benzyl bromide in 30 ml of dry THF was then added with ice-cooling, and the reaction solution was stirred with ice-cooling for 1 hour and at room temperature for 12 hours. Thereafter, the reaction mixture was poured into dilute HCl-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/ethyl acetate (50:1) mixture] to obtain 0.58 g of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=1>C(O)C>[CH2:21]([O:20][C:18]1[CH:17]=[CH:16][C:15]([S:28][C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 233a (62 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (24 mg, 47%). 1H NMR (300 MHz, DMSO-d6) ppm: 2.02 (s, 3 H) 2.75 (s, 3H) 5.15 (s, 2H) 6.29 (d, J=7.35 Hz, 1H) 7.12 (d, J=8.82 Hz, 2H) 7.16-7.27 (m, 2H) 7.29-7.52 (m, 8H) 7.78 (d, J=8.82 Hz, 1H) 8.36 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.82 Hz, 1H) 9.97 (s, 1H) 11.00 (s, 1H) 14.34 (s, 1H); MS (ESI+) m/z 507 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[C:8]2[CH:9]=[N:10][C:11]([CH2:21]Cl)=[C:12]([O:13]CC3C=CC=CC=3)[C:7]=2[CH2:6][O:5]1)[CH2:2][CH3:3].[CH3:23][NH2:24]>C1C=CC=CC=1>[CH2:1]([CH:4]1[C:8]2[CH:9]=[N:10][C:11]([CH2:21][NH:24][CH3:23])=[C:12]([OH:13])[C:7]=2[CH2:6][O:5]1)[CH2:2][CH3:3]
Reactant: CN
Reactant: CCCC1OCc2c1cnc(CCl)c2OCc1ccccc1
Solvent: c1ccccc1
Product: CCCC1OCc2c1cnc(CNC)c2O
Yield: 66 %

Procedure:
The method of example 1 was repeated, but starting with 1,3-dihydro-3-propyl-6-chloromethyl-7-benzoxy-furo-(3,4-c)-pyridine and gaseous methylamine dissolved in benzene. Yield 66% of an oily product, elemental analysis of which showed good correspondence with the formula C12H18N2O2.HCl.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]1[C:8]([O:13][CH3:14])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][CH2:21][C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH:10]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=Cc1ccncc1
Product: COc1cc(NCc2ccncc2)c(C(=O)O)cc1OC

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from 2-amino-4,5-dimethoxybenzoic acid (Aldrich) and pyridine-4-carbaldehyde. 13C-NMR (DMSO-d6) δ 169.4, 154.8, 149.6, 149.0, 147.5, 138.9, 122.1, 114.6, 101.4, 95.5, 56.1, 55.2, 45.0.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:9](=[CH:22][C:23](=[S:34](=[O:36])=[O:35])[CH:24]([CH3:33])[C:25]=1[C:26]1[CH2:30][CH:29]([CH2:31]Cl)[O:28][N:27]=1)[C:10]([C:12]1[C:17](=[O:18])[CH:16]([CH3:19])[CH2:15][CH:14]([CH3:20])[C:13]=1[OH:21])=[O:11].Cl>CS(C)=O>[CH3:7][C:8]1[C:9](=[CH:22][C:23](=[S:34](=[O:36])=[O:35])[CH:24]([CH3:33])[C:25]=1[C:26]1[CH:30]2[CH:29]([CH2:31]2)[O:28][N:27]=1)[C:10]([C:12]1[C:17](=[O:18])[CH:16]([CH3:19])[CH2:15][CH:14]([CH3:20])[C:13]=1[OH:21])=[O:11]
Reactant: CC1=C(C2=NOC(CCl)C2)C(C)C(=S(=O)=O)C=C1C(=O)C1=C(O)C(C)CC(C)C1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC1=C(C2=NOC3CC23)C(C)C(=S(=O)=O)C=C1C(=O)C1=C(O)C(C)CC(C)C1=O
Reaction time: 12 h

Procedure:
At room temperature, 0.27 g (2.4 mmol) of potassium tert-butoxide is added to a solution of 0.36 g (0.8 mmol) of 2-[2-methyl-3-(5-chloromethyl-4,5-dihydroisoxazol-3-yl)-4-methyl sulfonylbenzoyl]-1-hydroxy-4,6-dimethylcyclohex-1-en-3-one in 4 ml of dimethyl sulfoxide, and the mixture was stirred for 12 hours. The reaction mixture was then introduced into 300 ml of 3% strength hydrochloric acid. Following extraction with ethyl acetate, the combined organic phases were washed with water and dried, and the solvent was removed. This gave 0.21 g (63% of theory) of the title compound of melting point 90-96° C. 1H-NMR (δ in ppm): δ=1.0-1.6 (m, 10H), 2.18 (s, 3H), 2.4-2.5 (m, 2H), 2.77 (m, 1H), 3.20 (s, 3H), 5.18 (s, 1H), 7.31 (d, 1H), 8.02 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]\[S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O.Cl>C1COCC1>[OH:3][CH2:4][C:6]1[S:10][C:9](/[CH:11]=[CH:12]\[S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1cnc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 257 mg of 5-ethoxycarbonyl-2-((Z)-2-tritylthioethen-1-yl)thiazole in 10 ml of THF was cooled in ice, and 1.69 ml of a 1.0 M diisobutylaluminum hydride/toluene solution was added dropwise to the cooled solution under an argon atmosphere. The mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was adjusted to pH 2.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure to give 234 mg of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH:7]([CH:26]([CH3:28])[CH3:27])[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:30]([C:34]([OH:36])=[O:35])([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[F:31][C:30]([F:33])([F:32])[C:34]([OH:36])=[O:35].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:29])=[O:5])[CH:26]([CH3:28])[CH3:27])=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)C(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)C(NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-valine t-butyl ester (200 mg, 0.48 mmol) in CF3CO2H (1.5 mL) was stirred at 0° C. for 30 min, and at 23° C. for 1 h. The reaction mixture was diluted with PhMe, evaporated in vacuo, and the residue triturated with EtOAc to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-valine trifluoroacetate (170 mg, 0.36 mmol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:31]([F:34])([F:33])[F:32])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][C:25](Cl)=[CH:24][N:23]4[C:29]=3[CH3:30])=[O:19])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.C([O-])=O.[Na+]>>[NH2:1][C:2]1[O:3][C@H:4]([C:31]([F:34])([F:33])[F:32])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:20]3[N:21]=[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]4[C:29]=3[CH3:30])=[O:19])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: Cc1c(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc2ccc(Cl)cn12
Agent: O=C[O-]
Agent: [Na+]
Product: Cc1c(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)nc2ccccn12
Temperature: 110 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A sealable vial was charged with N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-6-chloro-3-methylimidazo[1,2-a]pyridine-2-carboxamide (0.0513 g, 0.102 mmol, Example 6), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (7.24 mg, 10.22 μmol) and sodium formate (21 mg, 0.307 mmol, Alfa Aesar). The sealed vial was evacuated and backfilled with nitrogen. DMF (1.3 ml) was added and the reaction was stirred in a preheated 110° C. oil bath for 1 hour. The reaction was cooled to RT and partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography using a gradient of 10-100% EtOAc in hexanes to afford the title compound as a white solid. (0.0385 g, 0.082 mmol, 81% yield). MS m/z=467.9 [M+H]+. Calculated for C21H18F5N5O2: 467.39