Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:9]([C@H:11]1[C@H:16]([C:17](=O)[N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][C@@H:13]([CH2:34][C:35](OC)=[O:36])[CH2:12]1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]([CH2:9][C@H:11]1[C@H:16]([CH2:17][N:18]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:15][CH2:14][C@@H:13]([CH2:34][CH2:35][OH:36])[CH2:12]1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1CC[C@@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)[C@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC[C@@H]1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](CN(Cc2ccccc2)Cc2ccccc2)C1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 109.7 %

Procedure:
To a cooled (−10° C.) solution of (racemic)-Methyl 2-[(1R,3R,4R)-3,4-bis(dibenzylcarbamoyl)cyclohexyl]acetate (8.18 g, 13.5 mmol) in THF (40 mL) is added, drop wise, lithium aluminum hydride (50 mL, 1M in THF). On complete addition, the cold bath is removed and stirring continued for 15 min. The resulting solution is heated to 55° C. and stirred at this temperature for 2.5 hr. This solution is cooled to 0° C. To the resulting solution is added, drop wise, water (1.9 mL) then NaOH (1.9 mL, 5M aqueous) then water (0.95 mL). The resulting mixture is diluted with Et2O (100 mL), filtered through Celite and the filtrate concentrated under vacuum to give the title compound as an oil (8.1 g). ESI-MS (m/z) 547 (MH)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:21]=[C:22]([C:26]#[CH:27])[CH:23]=[CH:24][CH:25]=1>>[C:26]([C:22]1[CH:21]=[C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:24][CH:23]=1)#[CH:27]
Reactant: C#Cc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: C#Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 56.4 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 201 mg of 3-aminophenylacetylene in place of the 2,4-difluoroaniline. 190 mg of N-(3-ethynylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=2)[C:17]([O:19]CC)=[O:18])[CH:7]=[CH:8][CH:9]=1>O1CCOCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=2)[C:17]([OH:19])=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc(OCc2cccc(Cl)c2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Temperature: 65 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
Lithium hydroxide (16.3 g, 389 mmol) was added to a solution of ethyl 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoate (79 g, 259 mmol) in 1,4-dioxane (1 L) and water (0.5 L). The reaction mixture was stirred at 65° C. for 5 hours, allowed to cool and stood at room temperature for 14 hours. The reaction was concentrated to remove the 1,4-dioxane, and the resulting brown aqueous solution was washed with diethyl ether (3×1 L). The aqueous layer was then acidified with 2N HCl (approximately 200 ml) and the resulting precipitate filtered and washed with water to give a yellow solid. This was dried overnight at 40° C. in a vacuum oven to give the title compound as a yellow solid (66.38 g). MS (ES−) [C15H1335ClO3—H]− 275. 1H-NMR (400 MHz, d6-DMSO) δ 2.43 (3H, s), 5.14 (2H, s), 7.10-7.13 (1H, m), 7.21-7.23 (1H, m), 7.38-7.47 (4H, m), 7.52 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][S:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])=[O:27]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[C:30]([NH:29][S:26]([CH3:25])(=[O:27])=[O:28])[CH:31]=[CH:32][CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(NS(C)(=O)=O)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 3.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylsulfonamido) phenylboronic acid (22 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)phenyl)methanesulfonamide (0.91 mg, 4%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.62 (m, 1H), 2.97 (s, 3H), 3.29 (s, 3H), 5.86 (m, 1H), 6.94 (m, 2H), 7.13 (m, 1H), 7.18 (m, 1H), 7.41 (m, 6H), 7.62 (m, 1H), 7.81 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O>CO.C(#N)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]>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:32]([O:31][CH3:27])=[O:33])[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CO
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(C(=O)OC)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
In a 50 ml pressure bottle, a solution of Example 1F (0.15 g, 0.238 mmol) and triethylamine (0.066 ml, 0.476 mmol) in methanol (2 ml) and acetonitrile (2 mL) was treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.017 g, 0.024 mmol). The mixture was pressurized with carbon monoxide (60 psi), and stirred at 60° C. for 4 hours. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel, eluting with dichloromethane, to provide the title compound. MS ESI(+) m/z 562.0 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OCC2C(C3C=CC=CC=3)=NOC=2C)C=1)=O.[NH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>>[N:49]1([NH:48][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1
Reactant: NN1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCOCC2)[nH]n1
Yield: 37 %

Procedure:
As described for example 1b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminomorpholine instead of morpholine, to the title compound (45 mg, 37%), which was obtained as a colorless oil. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[N+:16]([O-])=O)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[NH2:16])(=[O:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1ccc(NC(C)=O)c(N)c1

Procedure:
Methyl 4-acetamido-3-nitrophenylacetate (40 g, 0.159 mol)) was dissolved in methanol (400 ml) and hydrogenated at 5 bar over a 5% palladium on carbon catalyst. The catalyst was removed by filtration and the filtrate evaporated in vacuo to give methyl 4-acetamido-3-aminophenylacetate.
Reaction SMILES: [NH2:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C[Si](C)(C)NC(=O)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.CO>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:1][C:2]([CH3:14])([CH3:13])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: CC(C)(N)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(Cc1ccc([N+](=O)[O-])cc1)NC[C@H](O)c1cccc(Cl)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 108.8 %

Procedure:
A solution of 2.2 g of 2-amino-2-methyl-1-(4-nitrophenyl)propane (prepared by the procedures described in J. Milecki, et al. J. Med. Chem., 30, 1563 (1987)) and N-trimethylsilylacetamide (1.6 g) in 2.2 mL DMSO was stirred for 30 min, then (R)-3-chlorostyrene oxide (1.8 g) was added and the resulting solution was stirred at 95° C. for 22 h. The reaction solution was allowed to cool, poured over a mixture of ice (30 g) and 6 N aqueous hydrochloric acid (10 mL). A small portion of MeOH was added to produce a homogenous solution, which was stirred for 30 min. The resulting solution was basified with saturated aqueous sodium carbonate, extracted with ethyl acetate, the organic phase dried (Na2SO4) and concentrated in vacuo to afford 4.3 g of the title compound (I-1a) as an orange oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC1C=CC=CC=1C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:8]1([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Brc1ccccc1
Reactant: C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: c1ccc(N2CCNCC2)cc1
Temperature: 120 °C
Yield: 92 %

Procedure:
A 200 ml Kjeldahl flask equipped with a cooling condenser and a thermometer was charged with a solution of 22.0 g of piperazine in 20 ml of o-xylene, a solution of 6.70 g of bromobenzene in 20 ml of o-xylene, and a solution of 5.66 g of NaOBut in 20 ml of o-xylene, and further with a solution of 4.5 mg of palladium acetate in 5 ml of o-xylene (the ratio of palladium atom/bromobenzene=0.05% by mole). The flask was flushed with nitrogen for about 20 minutes while the content was stirred, and 0.2 ml of tri-tert.-butylphosphine was added. Then the mixture was heated to 120° C., and maintained at that temperature for 3 hours with stirring. After completion of the reaction, 80 ml of water was added to cool the reaction product. The mixture was introduced in a separatory funnel and the organic phase was separated. The lower aqueous phase was extracted with 40 ml of o-xylene. The organic phase was dried over sodium sulfate. Gas chromatographic analysis of the obtained product by the internal standard method revealed that the intended arylamine, i.e., N-phenylpiperazine was obtained in a yield of 92% by mole.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[C:27]([CH3:34])[N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl-].[NH4+]>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[C:29]([CH:28]=[C:27]([CH3:34])[N:26]=1)[C:31]([NH:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)[CH:3]=1)=[O:32]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (95 mg, 0.307 mmol) in N,N-dimethylformamide (5 mL) were added 2-chloro-6-methylpyridine-4-carboxylic acid (58 mg, 0.337 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (65 mg, 0.337 mmol) and 1-hydroxybenzotriazole (46 mg, 0.337 mmol), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/97→100/0) and precipitated from ethyl acetate/hexane to give the title compound (115 mg, 82%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].[C:13](OC(=O)C)(=O)C.O>CN(CN(C)C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH2:13])[C:10]([OH:12])=[O:11]
Reactant: COc1ccccc1CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Solvent: O
Product: C=C(C(=O)O)c1ccccc1OC
Temperature: 20 °C
Reaction time: 24 h

Procedure:
36.6 g of (2-methoxyphenyl)acetic acid, in suspension in 110 cm3 of bis(dimethylamino)methane, were cooled to a temperature in the region of 0° C. 110 cm3 of acetic anhydride were added dropwise, the temperature of the reaction mixture not exceeding 40° C. The reaction mixture was stirred for 24 hours at a temperature in the region of 20° C. and then cooled to a temperature in the region of 0° C. 500 cm3 of distilled water were then added and stirring was continued for 2 hours at a temperature in the region of 0° C. The solid which had appeared was separated by filtration, washed with three times 100 cm3 of distilled water and dried under reduced pressure at 40° C. 23 g of 2-(2-methoxyphenyl)propenoic acid were thus obtained in the form of a cream solid, the characteristics of which were as follows:
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CN(C=O)C.O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2=[O:1])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (7.50 g, 26.8 mmol) was dissolved in DMF (30 ml) and treated with potassium carbonate (7.40 g, 53.5 mmol) and 4-methoxybenzyl chloride (5.45 ml, 40.1 mmol). The mixture was stirred at ambient temperature overnight. The reaction was diluted with water (150 ml) and the solid that crashed out was collected by suction filtration. The solid was washed with water and dried to give diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (9.00 g, 84.0% yield) as a light green solid. MS(M+H)+ 401.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH:13]([OH:23])[C:14](=[O:22])[NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)[CH2:11][CH:10]([F:12])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC(CC1(C)CCCC1)C(N)=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[NH2:7][C:8]1([CH:13]([OH:23])[C:14]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:22])[CH2:11][CH:10]([F:12])[CH2:9]1
Reactant: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CC(F)C2)n1
Agent: CC1(CC(N)C(N)=O)CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1ccc(NC(=O)C(O)C2(N)CC(F)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 1-a (363 mg, 1.06 mmol) was treated with a 7.5 mL of a mixture of TFA:DCM:TIS:water (20:80:1:1). After 2 h at room temperature, LC/MS analysis confirmed complete removal of the Boc group and the solution was concentrated in vacuo and azeotroped with dichloromethane (3×) to remove excess TFA. The crude product (339 mg, 0.9 mmol) was dissolved in DCM (10 mL) and added to a solution of 2-amino-3-(1-methyl-cyclopentyl)-propionamide (prepared as described in Ex. 1 of WO2006/064286) (1.2 eq), PyBOP (1.2 eq) and diisopropylethylamine (4 eq) in DCM (5 mL) that had been stirred at room temperature for 5 min The mixture was stirred at room temperature until LC/MS analysis indicated complete amide formation (˜30 min) DCM was added to the reaction and the organic phase was washed with 0.1 M HCl (aq) (2×) and 10% NaHCO3 (aq) (2×). The organic phase was dried and concentrated in vacuo to afford the title compound which was used in subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11]>C(O)C.[Pd]>[NH2:14][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([OH:1])([CH3:17])[CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CC(C)(O)COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)COc1ccc(N)c(C(=O)O)c1
Yield: 99.3 %

Procedure:
A solution of 5-(2-hydroxy-2-methylpropoxy)-2-nitrobenzoic acid (0.145 g, 568 μmol) in ethanol (5 ml) was hydrogenated at normal pressure in the presence of 20 mg Pd/C 10% at r.t overnight. The catalyst was filtered and washed with EtOH. The filtrate was concentrated to give the title compound (127 mg, 99%) as grayish foam.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[O:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(F)c2)oc1C(C)C
Yield: 87.2 %

Procedure:
A solution of the aforementioned ester (92 mg, 0.265 mmol) in ethanol (5 ml) was added with 2 M aqueous sodium hydroxide (1 ml) to perform hydrolysis at room temperature for 4 hours, and extraction and recrystallization were performed to obtain the title compound (22, 77 mg, 86%) as colorless needles.
Reaction SMILES: B(F)(F)F.CCOCC.[CH3:10][O:11][C:12]([C:14]1[C:23]2[O:22][CH2:21][C:20](=O)[NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13].[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:10][O:11][C:12]([C:14]1[C:23]2[O:22][CH2:21][CH2:20][NH:19][C:18]=2[CH:17]=[CH:16][CH:15]=1)=[O:13]
Reactant: COC(=O)c1cccc2c1OCC(=O)N2
Agent: Cl
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1OCCN2
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Boron trifluoride diethyl etherate (10.1 mmol) is added dropwise to a mixture of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid methyl ester (4.83 mmol) in THF (12 mL) to keep the temperature below 5° C. After 20 min NaBH4 (10.1 mmol) is added and the mixture is stirred at 5° C. for 60 min. EtOAc (6.0 mL) and hydrochloric acid (1.0 M, 6.0 mL) are added dropwise. The mixture is made basic by addition of sat. aq. NaHCO3 solution, the layers are separated and the aq. layer is extracted with EtOAc. The combined organic layers are dried over MgSO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.69 min; [M+H]+=194.0.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11]3[NH:19][C:18]4[C:13](=[N:14][C:15]([F:21])=[N:16][C:17]=4[NH2:20])[N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1C(=O)N([Cl:29])C(=O)C1>CN(C=O)C>[F:21][C:15]1[N:14]=[C:13]2[C:18]([NH:19][C:11]([CH2:10][C:8]3[C:7]([Cl:29])=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:12]2)=[C:17]([NH2:20])[N:16]=1
Reactant: Nc1nc(F)nc2nc(Cc3ccc4c(c3)OCO4)[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Nc1nc(F)nc2nc(Cc3cc4c(cc3Cl)OCO4)[nH]c12

Procedure:
A solution of 8-Benzo[1,3]dioxol-5-ylmethyl-2-fluoroadenine (20 mg, 0.07 mmol), NCS (35.6 mg, 0.27 mmol) in anhydrous DMF (0.4 mL) was stirred at room temperature for 2.5 h. Following solvent removal, the product (11 mg, 48.8%) was collected through silica gel column purification (CHCl3:EtOAc at 9:1 to 5:5). 1H NMR (400 MHz, DMSO-d6) 7.40 (bs, 2H), 6.97 (s, 1H), 6.89 (s, 2H), 5.97 (s, 2H), 4.04 (s, 2H); MS m/z 322.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.[CH2:9]([O:11][C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])[CH3:10]>C1COCC1>[NH2:1][C:2]1[S:3][C:4](/[CH:7]=[CH:14]/[C:12]([O:11][CH2:9][CH3:10])=[O:13])=[CH:5][N:6]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(C=O)s1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cnc(N)s1
Temperature: 65 °C
Yield: 60.5 %

Procedure:
2-Aminothiazole-5-carbaldehyde (0.25 g, 2 mmol) was dissolved in anhydrous THF (20 mL). (Ethoxycarbonylmethylene)triphenylphosphorane (0.790 g, 2.2 mmol) was added at room temperature and the reaction mixture was heated overnight at 65° C. The reaction mixture was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 50-80% EtOAc in Hexanes to provide pure (E)-ethyl 3-(2-aminothiazol-5-yl)acrylate (0.24 g) as a white solid. ES+(M+H)+199.
Reaction SMILES: C12BC(CCC1)CCC2.FC(F)(F)S(O[C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([Cl:24])=[CH:18][C:17]=1[CH2:25][CH:26]=[CH2:27])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+].OO>O1CCCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:24][C:19]1[CH:18]=[C:17]2[C:16]([CH2:27][CH2:26][CH2:25]2)=[C:21]([O:22][CH3:23])[CH:20]=1
Reactant: C=CCc1cc(Cl)cc(OC)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: B1C2CCCC1CCC2
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(Cl)cc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To 9-borabicyclo[3.3.1]nonane (130 mL, 0.5 M in tetrahydrofuran) cooled to 0° C. was added 2-allyl-4-chloro-6-methoxyphenyl trifluoromethanesulfonate (16.5 g, 0.050 mol) in tetrahydrofuran (100 mL), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (1.5 g, 1.84 mmol), and potassium phosphate (16.0 g, 0.075 mol) and the reaction mixture was heated at reflux for 20 h. The reaction mixture was allowed to cool to room temperature and aqueous sodium hydroxide (2.5 N, 30 mL) was added followed by hydrogen peroxide (30 wt. %, 25 mL) and stirring was continued for 1 h. The solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, hexanes) provided 6.2 g (68%) of 6-chloro-4-methoxyindane as a white solid. mp 38-40° C.; Anal. calcd. for C10H11ClO: C, 65.76; H, 6.07. Found: C, 66.08; H, 6.11.