Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[O:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([CH3:46])=[C:42]([CH2:44][NH2:45])[CH:43]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]([NH:45][CH2:44][C:42]2[CH:43]=[C:38]([Cl:37])[CH:39]=[CH:40][C:41]=2[CH3:46])=[O:9])[O:4][N:3]=1
Reactant: Nc1cc(C(=O)O)on1
Reactant: Cc1ccc(Cl)cc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Cl)cc1CNC(=O)c1cc(N)no1
Reaction time: 0.08 h
Yield: 71.5 %

Procedure:
To a solution of 3-aminoisoxazole-5-carboxylic acid (492 mg, 3.84 mmol) in DMF (16 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.87 g, 4.22 mmol) at 0° C. The resulting solution was stirred for 5 min, after which time, 1-(5-chloro-2-methylphenyl)methanamine (598 mg, 3.84 mmol) and N,N-diisopropylethylamine (2.0 mL, 12 mmol) was added. The solution was stirred at room temperature for 0.5 h. The reaction solution was diluted with ethyl acetate and water, the organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was recrystallized with ethyl acetate and hexanes to give product (730 mg, 71%). LCMS calculated for C12H13ClN3O2(M+H)+: m/z=266.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([NH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4]>[OH-].[Na+]>[CH2:19]([O:18][C:16]([NH:15][CH:11]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]1=2)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2c(c1)CCCC2NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC1CCCc2cc(C(=O)O)ccc21)OCc1ccccc1
Yield: 83.2 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 8 using 5-(benzyloxycarbonylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (3.50 g) and 1N aqueous sodium hydroxide solution (20 ml), the objective 5-(benzyloxycarbonylamino)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2.79 g) was obtained as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>CO.[Ni]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH:20]3[CH2:21][CH2:22]3)=[O:19])[CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])nc2)ccn1)C1CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
A solution of N-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (1.50 g, 5.00 mmol) in MeOH (30 mL) was treated with hydrazine hydrate (1.50 g, 30.0 mmol) followed by Raney nickel (0.300 g, 5.11 mmol) and stirred at RT for 3 h. The solids were removed via filtration through diatomaceous earth, rinsed with DCM, then MeOH and the filtrate concentrated to dryness to afford N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)cyclopropanecarboxamide (1.17 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.06 (m, 1H), 6.92 (d, J=8.9 Hz, 1H), 6.43 (s, 2H), 2.37 (m, 1H), 1.18 (s, 4H); MS (ESI) m/z: 271.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.C(=O)(O)[O-].[K+].[C:37]([O:43][CH2:44]Cl)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:12]([NH:13][C:14](=[O:23])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11](=[O:24])[N:6]2[C:7]=1[C:8]([O:10][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:9]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 81.6 %

Procedure:
3-Methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylic acid (69.6 g., 0.2 mole) was dissolved in 300 ml. of dimethylformamide and reacted in sequence with triethylamine (20.2 g., 0.2 mole), potassium bicarbonate (40 g., 0.4 mole) and chloromethyl pivalate (33 g., 0.22 mole) according to procedures detailed in Preparation 1. To isolate the product, the reaction mixture was diluted with 3 l. of ether, and the organic solution washed, dried and evaporated to dryness, as detailed in Preparation 1, affording pivaloyloxymethyl 3-methyl-7-(2-phenoxyacetamido)ceph-3-em-4-carboxylate [75.5 g., 82%; ir (CH2Cl2) 1776, 1750, 1685 cm-1 ].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([CH3:18])[N:11]=[C:10]([CH3:19])[C:9]=1[C:20]([O:22]C)=[O:21].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:20]([OH:22])=[O:21])=[C:10]([CH3:19])[N:11]=[C:12]([CH3:18])[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1c(C)nc(C)c(C(=O)OC)c1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C)c(C(=O)O)c(-c2ccccc2F)c1C(=O)O
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A mixture containing 69 g of dimethyl 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate, 300 ml of methanol and 100 ml of 35% aqueous sodium hydroxide solution was refluxed with stirring for 5 hours and then allowed to stand at room temperature overnight. The methanol was removed using a rotary evaporator and to the residual liquid was added 200 ml of water and filtered. The filtrate was acidifed with concentrated hydrochloric acid whereupon there precipitated a cream colored solid, which was washed with water and dried at 80°-85° C. to yield 52.6 g (88%) of 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid, m.p. >285° C.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:12]Br>CCOCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][Br:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCC[C@H]1CC[C@H](CO)CC1
Solvent: CCOCC
Product: CCC[C@H]1CC[C@H](CBr)CC1
Temperature: 180 °C

Procedure:
Trans-4-n-propylcyclohexylmethanol (0.12 mole) was added to red phosphorus (0.03 g atom) and warmed gently (ca 30° C.) using an oil bath. Bromine (0.14 mole) was added dropwise to the mixture. When addition was complete (about 1/2 hour) the temperature of the oil bath was raised to 180° C. for one hour. After this time, the mixture was allowed to cool, shaken with ether and filtered. The filtrate was washed with water, then dried (Na2SO4). The ether was removed by distillation and the residue distilled. The product boiled at 112° C. at a pressure of 15 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH2:15])[C@H:8]([O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2].[CH3:22][CH2:23][O:24]C(C)=O.C([O-])(O)=O.[Na+].C(OC(=O)C)(=O)C>CCCCCC.COC(C)(C)C>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([N:12]=[N+:13]=[N-:14])[C@@H:9]([NH:15][C:23](=[O:24])[CH3:22])[C@H:8]([O:16][CH:17]([CH2:18][CH3:19])[CH2:20][CH3:21])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N)[C@@H](N=[N+]=[N-])C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 118.5 mg of 28 and 1.0 mL of EtOAc in a 5.0 mL round-bottom flask equipped with a magnetic stirrer and an inert gas supply was added 1.0 mL of aqueous 1 M NaHCO3. To the stirred mixture was added 45.4 μL of acetic anhydride and the mixture was stirred for 1 h at RT. The organic phase was separated and dried (Na2SO4, 1 g), filtered and the filter cake was washed with 2.0 mL EtOAc. The combined filtrates were evaporated at 40° C./240 to 10 mbar to afford 139 mg crude product as beige solid. The solid was suspended in 1.40 mL of n-hexane and 0.70 mL tert-butyl methyl ether, stirred for one h at RT, cooled to 0-5° C. and stirred for 2 h at 0-5° C. The suspension was filtered and the filter cake was washed with total 0.70 mL of a pre-cooled (0-5° C.) mixture of n-hexane and tert-butyl methyl ether (2/1). The filter cake was dried at 45° C./9 mbar to afford 94 mg of 30 as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:9][CH:10]=1)=[O:4].[OH:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37].C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:26][N:27]2[C:31](=[O:32])[C:30]3[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:28]2=[O:37])=[CH:9][CH:10]=1)=[O:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(OCCCON2C(=O)c3ccccc3C2=O)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 68.6 %

Procedure:
This compound was produced using similar methods as those used in Step 1, example 4, starting with 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.60 g, 1.46 mmol), N-hydroxyphthalimide (0.30 g, 1.86 mmol) and N,N-diisopropylethylamine (0.36 g, 2.88 mmol). The crude material was purified by flash chromatography through silica gel using methylene chloride to give 6-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-propoxy]-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.50 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6); δ 8.01 (dd, 1H), 7.88 (d, 1H), 7.84 (s, 4H), 7.74 (s, 4H), 7.31 (d, 1H), 4.31 (t, 2H), 4.22 (t, 2H), 3.82 (s, 3H), 2.09 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:21]2[CH:22]=[CH:23][C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])=[CH:19][C:20]=2[Cl:25])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Br)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(Br)cc(CC(=O)O)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (v) and the product from example 3 step (i).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[OH:38][C:39]([CH3:43])([CH3:42])[C:40]#[CH:41]>C1(C)C=CC=CC=1.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.[Cu]I>[Cl:27][C:19]1[CH:18]=[C:17]([C@@H:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:41]#[C:40][C:39]([OH:38])([CH3:43])[CH3:42])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(O)C#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A suspension of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 486 mg, 1.0 mmol) in toluene (8 mL) was treated with N,N-diisopropylethylamine (2 mL), 3-hydroxy-3-methylbutyne (168 mg, 2.0 mmol), dichlorobis(triphenylphosphine)palladium(II) (40 mg), and copper(I) iodide (20 mg). The mixture was stirred at 25° C. overnight, and an oily black precipitate was obtained. The top clear solution was decanted, and the oily precipitate was rinsed first with toluene (5 mL) and then with hexanes (5 mL). The residue was dissolved in methylene chloride and extracted with methylene chloride and a 0.2N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, elution with 1/1 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-hydroxy-3-methyl-but-1-ynyl)-pyrazin-2-yl]-propionamide (412 mg, 84%) as a fluffy solid: (ES)+-HRMS m/e calcd for C24H28ClN3O4S (M+H)+ 490.1562, found 490.1553.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[N:6][CH:7]=1.Cl.N[C@H]1CCC[C@@H]1N[C:36](=[O:48])C1C=CC=CC=1N1N=CC=N1.BrC1C=C(OC)C(Cl)=NC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([O:48][CH3:36])[C:5]([NH:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]2[N:26]=[CH:25][CH:24]=[N:23]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(Br)cn1)c1ccccc1-n1nccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cc(Br)cnc1Cl
Product: COc1cc(Br)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1
Temperature: 100 °C

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-[(5-bromopyridin-2-yl)amino]cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 118) from N-[(1S,2S)-2-amino cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 4; 300 mg, 0.98 mmol) and 5-bromo-2-chloro-3-methoxypyridine (CAS number 286947-03-3; 260 mg, 1.17 mmol) except after heating overnight, to this was then added further 5-bromo-2-chloro-3-methoxypyridine (CAS number 286947-03-3; 260 mg, 1.17 mmol), sodium tert-butoxide (150 mg, 1.56 mmol), BINAP (24 mg, 0.039 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18 mg, 0.019 mmol) and the reaction was heated at 100° C. for 3 hours. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The aqueous layer was further extracted with ethyl acetate (3×10 ml). The combined organics were washed with brine, filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(-c2ccco2)c1
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-2-yl)aniline.hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%). Note that 3-(furan-2-yl)aniline.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([F:15])([F:14])[F:13])[C:6]([C:16]([N:18]1[CH2:23][CH2:22]O[CH2:20][CH2:19]1)=[O:17])=[CH:5]2.Cl.[F:25][C:26]1([F:32])CCNCC1>>[F:25][C:26]1([F:32])[CH2:20][CH2:19][N:18]([C:16]([C:6]2[N:7]([CH2:11][C:12]([F:15])([F:13])[F:14])[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:17])[CH2:23][CH2:22]1
Reactant: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCC(F)(F)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 5-hydroxy-1-(2,2,2-trifluoro-ethyl)-1H-indole-2-carboxylic acid (Intermediate 1, step 3) and 4,4-difluoropiperidine hydrochloride. The title product was obtained in 80% as white solid. MS (m/e): 361 (M−H−, 100%).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([C:15](=O)[C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[C:6]([CH2:10][C:11](OC)=[O:12])[CH:7]=2)[O:2]1.O.[NH2:27][NH2:28].C(O)(=O)C>C(O)C>[CH2:1]1[O:2][C:3]2=[CH:4][C:5]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:28][NH:27][C:11](=[O:12])[CH2:10][C:6]=3[CH:7]=[C:8]2[O:9]1
Reactant: NN
Reactant: COC(=O)Cc1cc2c(cc1C(=O)c1ccc([N+](=O)[O-])cc1)OCO2
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Yield: 47.3 %

Procedure:
A solution of methyl 4,5-methylenedioxy-2-(4-nitrobenzoyl)phenylacetate (90 mg, 0.26 mmol), hydrazine hydrate (50 μL, 0.88 mmol), and acetic acid (40 μL) in ethanol (15 mL) was refluxed for 4 days. A yellow solid precipitated out from the solution. After cooling, the solvent was removed via pipette and the solid was washed with EtOAc (twice) and hexane, dried in vacuo to provide the title compound (40 mg, 47%), mp: 293°-295° C. 1H NMR (DMSO-d6) 11.2 (s, 1H), 8.31(d, 2H, J=8.8), 7.79 (d, 2H, J=8.8), 7.13 (s, 1H), 6.65 (s, 1H), 6.12 (s, 2H), 3.45 (s, 2H). Anal. Calcd. for C16H11N3O5 : C, 59.08; H, 3.41; N, 12.92. Found: C, 59.05; H, 3.43; N, 2.83.
Reaction SMILES: C(O[C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.N[C@H](C1C=CC(OC[C@H](O)CO)=CC=1)C(N[C@@H]([C@H](C1C=CC=CC=1)C)C(NC1C=CC(I)=CC=1Cl)=O)=O.C(OC(N[C@@H]([C@H](C1C=CC=CC=1)C)C(O)=O)=O)(C)(C)C.[C:90]([O:94][C:95]([NH:97][C@H:98]([C:102]1[CH:107]=[CH:106][C:105]([O:108][CH2:109][C@H:110]2CO[C:112](C)(C)[O:111]2)=[CH:104][CH:103]=1)[C:99]([OH:101])=[O:100])=[O:96])([CH3:93])([CH3:92])[CH3:91]>>[C:90]([O:94][C:95]([NH:97][C@H:98]([C:102]1[CH:103]=[CH:104][C:105]([O:108][CH2:109][CH2:110][O:111][CH3:112])=[CH:106][CH:107]=1)[C:99]([OH:101])=[O:100])=[O:96])([CH3:93])([CH3:92])[CH3:91]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Agent: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C[C@@H](c1ccccc1)[C@H](NC(=O)[C@H](N)c1ccc(OC[C@H](O)CO)cc1)C(=O)Nc1ccc(I)cc1Cl
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodoaniline was used in place of 4-bromo-2-chloroaniline in step 1, (ii) (2S,3S)-2-tert-butoxycarbonylamino-3-methyl-pentanoic acid was used in place (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, and (iii) (R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-Butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 80.
Reaction SMILES: N1C=C2C(N=CN2)=NC=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13]([Cl:20])[N:12]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(N(CC)CC)C>ClCCl>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C:25]2[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=2)=[C:13]([Cl:20])[N:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: c1ncc2[nH]cnc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-n2cnc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
Purine N9 arylation via boronic acids/cupric acetate: A 20 mL glass vial equipped with a magnetic stir bar was charged with 2,6-dichloropurine (0.200 g, 1.06 mmol, 1.0 equiv), 4-methylphenylboronic acid (0.288 g, 2.12 mmol, 2.0 equiv), anhydrous cupric acetate (0.384 g, 2.12 mmol, 2.0 equiv.), 4 Å activated molecular sieves (0.500 g), triethylamine (0.443 mL, 3.18 mmol, 3.0 equiv.) and dichloromethane (5.0 mL). The reaction was stirred under air at ambient temperature and monitored by TLC. When the reaction was complete after 24 hours, it was filtered through Celite, washed with methanol and purified by flash column chromatography (1% methanol in dichloromethane) to afford desired 2,6-dichloro-9-(4-methylphenyl)-purine (0.136 g, 47%). 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 7.41 (d, 2H, J=8.1 Hz), 7.54 (d, 2H, J=8.1 Hz), 8.35 (s, 1H); HRMS (MALDI-FTMS) C12H8Cl2N4 [MH+] 279.0199, found: 279.0208.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:19])[CH:11]=[CH:12]C1C=CC=CC=1.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.N1C=CC=CC=1>[F:9][C:6]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]2[C:5]=1[CH:12]=[CH:11][C:10](=[O:19])[NH:4]2
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1ccc2c(F)ccc(F)c2[nH]1
Yield: 20.7 %

Procedure:
10 g of 2,5-difluoroaniline and 6 g of pyridine in 350 ml of dichloromethane are mixed drop by drop at 0° C. with 12.9 g of cinnamic acid chloride and stirred until conversion is completed at 0° C. The batch is added to 2N hydrochloric acid, and it is extracted with dichloromethane. It is washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The solid that is obtained is mixed with 11.1 g of aluminum chloride and heated for 8 hours to 150° C. After chromatography on silica gel, 2.9 g of 5,8-difluoroquinolin-2(1H)-one is obtained. The latter is reacted in 100 ml of ethylene glycol in the presence of 780 mg of copper(II) oxide for 20 hours at 200° C. in ammonia atmosphere at 60 bar. After chromatography on silica gel, in this case 5-amino-8-fluoroquinolin-2(1H)-one is obtained as fraction A and 2,5-diamino-8-fluoroquinoline is obtained as fraction B.